Good Laboratory practices

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Good Laboratory Practices:

Good Laboratory Practices Sam T Varghese 1 st yr M.Pharm Drug Regulatory affairs NGSMIPS, Mangalore

GLP: GOOD LABORATORY PRACTICE:

GLP: GOOD LABORATORY PRACTICE Definition : Good Laboratory Practice is a quality system concerned with the organizational process and the conditions under which a study is planned, performed, monitored, recorded, archived & reported. There are some simple rules such as: Say What You Do (with written standard operating procedures), do what you say (follow the procedures), be able to prove it (with good record keeping)

GLP:

GLP Planned : the study plan (protocol) & to planned changes throughout studies. Performed : refers to standard operating procedures, which are GLP requirement. Recorded : collection of raw data and the recording of deviations, if any during the studies. Reported : study reports didn't always reflect the study data accurately , assuring accuracy in the report has now become essential part of GLP. Archived : the study data, specimens, samples and reports are properly archived. Monitored : by study staff, quality assurance personnel and national inspectors helps to assure GLP compliance.

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GLP is a formal regulation that was created by the FDA (United states food and drug administration) in 1978 . 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. HISTORY

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THE BIRTH OF GLP In the early 70’s FDA became aware of cases of poor laboratory practice all over the United States. FDA decided to do an investigation on 40 toxicology labs. They discovered a lot fraudulent activities and a lot of poor lab practices. The FDA published their findings on investigation summarized in following slide.

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Poorly-trained Study Directors and study personnel Poorly-designed protocols Protocols not followed - procedures not conducted as prescribed Raw data badly collected - not correctly identified –without traceability - not verified or approved by responsible persons Lack of standardized procedures Poor animal husbandry Inadequate characterisation of test items and test systems Inadequate resources Reports not sufficiently verified, inaccurate account of raw data Inadequate archives and retrieval processes FDA INVESTGATION FINGINGS

FAMOUS EXAMPLE:

FAMOUS EXAMPLE One of the labs that went under such an investigation made headline news. The name of the Lab was Industrial Bio Test, that ran tests for big companies such as Procter and Gamble. It was discovered that mice that they had used to test cosmetics such as lotion and deodorants had developed cancer and died. Industrial Bio Test lab threw the dead mice and covered results deeming the products good for human consumption. Those involved in production, distribution and sales for the lab eventually served jail time .

OBJECTIVES OF GLP OR WHY GLP? :

OBJECTIVES OF GLP OR WHY 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. Promote the quality and validity of data generated in the testing of chemicals. Protection of human health and the environment. Assurance of quality and validity of test data. Animal welfare.

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SCOPE OF GLP Non-clinical safety testing of test items contained in Pharmaceutical products Pesticide products Cosmetic products Veterinary drugs Food and feed additives Industrial chemicals

FUNDEMENTALS OF OECD GLP PRINCIPLES:

FUNDEMENTALS OF OECD GLP PRINCIPLES Resources • personnel, facilities & equipment Rules • guidelines, procedures, protocols Characterization • test article, identification, quality test system Documentation • raw data, final report, archives Quality assurance • Advice, audit, inspection, training

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Curriculum vitae Training records job descriptions RESOURCES MANAGEMENT PERSONNEL Good science Good organization (calibration) (suitability ) (dose mixing unit) (animal facilities) Buildings Equipments FACILITIES/EQUIPMENTS

1.A MANAGEMENT:

1.A MANAGEMENT Basic factor of GLP Responsibility for conduct and interpretation of the study, including all scientific and organizational aspects. Has responsibility for promoting Good science Good organisation Good science Experimental design Based on known scientific principles Knowledge of experimental variables/bias Interpretation of results

GOOD ORGANISATION:

GOOD ORGANISATION Planning of studies and resource allocation Adequate physical facilities Sufficient qualified staff- requirement Definition of staff responsibilities Staff training Ensuring proper conduct of training Good record keeping & organized archives Sufficient physical resources and personnel MASTER SCHEDULE All studies should be included Have only 1 official schedule Include actions like Protocol review & report preparation Keep up-dated

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l lo DA DATES STUDY INFORMATION Study no Study director Title Protocol review Start date End In-vivo Draft Report audit Final Report review location archive Comments • Define the system in an SOP • Decide who should maintain this document • Archive - as necessary • Distribute to those who need it MASTER SCHEDULE TEST ITEM : ……………….

1.B PERSONNEL:

1.B PERSONNEL Organisation charts, reporting relationships Curriculum vitae Training records Job description s ORGANISATION CHARTS Should give a good idea of how the organisation operates Keep it simple Add functional responsibilities only if this helps to explain the organisation

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CURRICULUM VITAE For all personnel In standard format Up-to-date / archived Contains : - qualifications/education/diplomas - professional experience It should contain following information – name, age and sex of the person; – education, including all qualifications awarded by recognized institutions; – professional experience both within the institution and before joining it; – any publications; –membership of associations; – languages spoken.

TRAINING RECORDS:

TRAINING RECORDS Past • Induction to the job • Competence of personnel regarding SOPs • External courses / internal courses • Attendance at congresses/seminars may be included Future • Training plans for each member of staff Up-to-date archived JOB DISCRIPTION Clearly define day-to-day responsibilities and tasks • Make it clear who reports to whom • Describe delegation of tasks • Must be up-to-date • Standard format • Best signed by "n" and "n + 1“

1.C BULDINGS / FACILITIES:

1.C BULDINGS / FACILITIES Two examples : Dose mixing unit Animal facilities The way to protect studies from contamination, disturbance or interference is to ensure separation between studies, test systems, operations and test items. Operations Studies Test Items Test Systems S E P E R A T I O N S E P E R T I O N Adequate separation is needed Physical separation • Rooms • Cabinets / isolators • Air systems and filters Separated by organisation • Defined work areas • One-way systems • Different activities in same areas at different times • Cleaning between activities • Separate staff

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DOSE MIXING UNIT Deals with test and control items and their : Receipt Storage Dispensing Weighing Mixing Dispatch SIZE • Accommodates all activities (including paperwork) without risk of mix-ups or cross contamination • Sufficient working area, separate storage and waste disposal CONSTRUCTION • Materials allow for easy cleaning • Air flow / filters protect test items & personnel LOCATION- Separate areas for • Storage of test materials under different conditions • Storage of control materials • Handling volatile materials • Weighing areas • Mixing different dose forms (e.g. diet & liquid) • Storage of prepared dose • Cleaning equipment • Offices - rest rooms / changing rooms

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ANIMAL HOUSE FACILITIES Design should : Reduce risk of test system : • being affected by environmental variables • encountering disease • encountering other test articles Separate activities where possible, use barriers ANIMAL ROOM Waste ( eliminate promptly) Staff (changing/ shower procedure) Air (pressure diff & filters) Temperature Food (not contaminated) Water (clean supply) Bedding ( dust free, autoclaved) Animals (health status/quarantine) Dose mixes ( pharmacy) Noises Cages (wash , autoclave)

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BULDINGS AND EQUIPMENTS Maintenance Documentation MAINTENANCE Preventive maintenance Curative maintenance (fix it when it breaks) Back-up equipment / procedures Contracts with external service organizations Alarms Service plan (plan title) year Jan. Feb. Mar. Apr. May Jun. Jul. Aug. Sep. Oct. Nov. Dec. check airflow alarm D D D D d d d d d d d d D D D D d d d d d d d d D D D D d d d d d d d d M M M m m m m m m m m m X x x x x x Check air intakes Check lane working Check drive belts Lubricate fans Record air flows

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DOCUMENTATION Keep records of : Use – logbook Qualification calibration / checks Maintenance service plan Fault action reports SOPs Qualification report Logbook Service reports Fault action report COMPUTERISED SYSTEMS Training Facilities Equipment Maintenance & disaster recovery Security Validation

:

characterization principally concerns TEST ITEM TEST SYSTEM The test item active ingredient for a medicine, a pesticide, a food additive, a vaccine, a chemical compound used industrially, a biomass, an extraction from plant tissue, etc. GLP requires that procedures guarantee that the dose formulation administered is made with the right test item, at the right concentration and in the same way each time. The analytical laboratory provides results that are used to demonstrate that the correct dose of the correct test item has been made prior to administration to the test systems. TEST ITEM CHARACTERIZATION

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TEST SYSTEMS The test system could be an animal, a plant, a bacterium, an isolated organ, a field or other ecosystem or even analytical equipment, etc. Physical and chemical test systems Appropriate design and adequate capacity of apparatus used for the generation of data Integrity of physical/chemical test systems Biological test systems Proper conditions for storage, housing, handling and care Isolation of newly received animal and plant test systems until health status is evaluated Humanely destruction of inappropriate test systems

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ANIMALS -ACCLIMATIZATION Acclimatization period depends on species/ protocol Health check at specified times Document preparation When the animals are ready for the study, the study room is cleaned, disinfected, supplied with feed etc. Transport stress can introduce important variables into the study and have a significant effect on the health of the animals. Keep letters, invoices, supply and delivery notes from the suppliers as raw data GLP says study report must contain “….a description of all circumstances that may have affected the quality of data…”

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RULES 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. 2 main types of prescriptive documents: The protocol (or study plan) : The protocol is a high level document which defines the study design. Standard Operating Procedures (SOP) : SOPs are instructions on how to perform the routine procedures that make up a good part of the study.

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PROTOCOL OR STUDY PLAN It’s a pivotal document why the study is being performed, how the work will be organized, what data will be collected during the experiment who is responsible for the various aspects of the study . Approval /Review Approved and dated by study director before study starts Allow time for protocol review by QA Allow times for correction Allow time for distribution to study staff Allow time for pre-study meeting

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Study Director Sponsor Management Main file Archives Quality assurance unit Animal husbandry Technician in charge Analytical laboratory Clinical pathology Necropsy Pathology Statistician PROTOCOL CIRCULATION LIST RECEIVED DATE The study director signs and dates the protocol to approve it.

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STANDARD OPERATING PROCEDUR (SOP) Approved SOP’s to ensure the quality and integrity of the laboratory data The SOP must be followed exactly, otherwise there is increased test-to-test variability, no traceability and no auditability . Deviations from SOP’s to be acknowledged by the study director Established procedure to be followed in carrying out a given operation or in a given situation. For successive implementation of SOP : Management support – company culture Training to SOPs SOP management

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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 Record keeping, reporting, storage and retrieval Coding system, data collection, preparation of reports, indexing system, Test system Room preparation, environmental room conditions, receipt transfer, Quality Assurance Procedures Operation of QA personnel

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RESULTS These are DESCRIPTIVE documents They give us the results of the experiment They tell us who did , what, when, where and how RESULTS Raw Archives Data Study reports RAW DATA Original record (first, on spot) Needed for study reconstruction Lost/ Inaccurate data may invalidate the study Collect data on prepared forms, so they indicate During the study process , should follow protocol & SOP. Data should be record, directly, promptly, accurately, legibly During recording process, never use pencils & ‘white out’, never correct data if you do not explain why, sign and date every changes “ WHAT” was done “HOW” it was done “WHEN” it was done & “WHO” collected the data

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FINAL REPORT Final reports should be signed by study director. Once its been signed, it cannot be changed. Modifications by amendments only. The amendment must indicate what is being changed or added to the report and why the modification is being made. The amendment must be signed by the study director and must be audited by the QAU must include the following contents • name and address of test facility • dates of start and finish of the study • name of study director • objectives of the study • details of test items and vehicles • description of the test system • details of dosing, route & duration • summary of findings • discussion • conclusion • references • GLP compliance statement frm study director • QA statement of inspections/audits • signed/dated report from contributing scientists

ARCHIVES :

ARCHIVES Is not a simple place for storage of old materials Safe depository of invaluable information. What is left at the end of the study is used todemonstrate the validity and traceability of the scientific results. FUNCTON Long term , secure storage and fast retrieval of data Contains all original scientific data, master documents reports, etc.. Endpoint of regulated work SECURITY Only authorized entry permitted – per SOP Examination in-situ of documents is preferred Protection against fire, flood and vandalism if possible

ARCHIVES :

ARCHIVES SUBMISSION FORM HISTORY/EVENT FORM DEPT/GROUP : Holding no : PROJECT : STUDY NO : Quantity Description Comments Date signature of submitter signature of archiver DATE EVENT AUTHORISATION

QUALITY ASSURANCE UNIT:

QUALITY ASSURANCE UNIT a group of persons with a set of defined duties that ensures management that all the quality processes implemented in an institution are functioning correctly monitor all pre-clinical studies declared to support an application for research or marketing permits for products regulated by the FDA to assure management that facilities, equipment, personnel, methods, practices, records, and controls are in conformance with the regulations in Title 21 Code of Federal Regulations of the Food and Drug Administration Part 58 Good Laboratory Practice for Non Clinical Laboratory Studies RESPONSABILITIES Assure study plan & SOPs are available Ensure study plan & SOPs are followed by 1 ) Inspection 2 ) Audit Record finding in writing Review final report Prepare / Sign QA statement

INSPECTION AND AUDIT:

INSPECTION AND AUDIT Study based Facility/System based Process based STUDY BASED Protocol/study plan On-going (usually critical phases) Report (with respect to raw data) FACILITY / SYSTEM BASED Buildings / equipments / metrology Support services Computer systems Personnel training / documentation PROCESS BASED Inspection of processes which occur frequently, eg Slide preparation Reading Ames test Measuring food consumption

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QA INSPECTION REPORT QUALITY ASSURANCE STATEMENT Date of inspection Date of findings to Study manager & Management Phases audited Sign only if GLP compliance statement from study director is considered justifiably and all corrective actions have been completed HEADER Phase QA comments response Audited acton planned Signature Date Signature Date

What happens if a workplace does not comply with federal Good Laboratory Practice standards?:

What happens if a workplace does not comply with federal Good Laboratory Practice standards?

Disqualification of a Facility :

Disqualification of a Facility Before a workplace can experience the consequences of noncompliance, an explanation of disqualification is needed The FDA states 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

Consequences of Noncompliance:

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. Once finally disqualified, the facility may not receive or be considered for a research or marketing permit and the study is rejected

Upon Disqualification…:

Upon Disqualification… The commissioner may notify the public and all interested persons, including other federal agencies the facility may have contacted 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 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

Reinstatement of a Disqualified Facility:

Reinstatement of a Disqualified Facility The commissioner can be certain that future studies will be conducted in compliance with the Good Laboratory Practice standards. The disqualified facility will be required to put in writing to the commissioner reasons why it should be reinstated and any actions the facility will take or have taken to assure any disqualification problems will not happen again

Reinstatement of a Disqualified Facility:

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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CONCLUSION Describes good practices for non-clinical lab studies that support research or marketing approvals for FDA-regulated products Support the development of quality and validity of test data used for determining the safety of chemicals and chemicals product. Good laboratory practice” can be considered as “ essentially tidiness, cleanliness, hygiene and common sense Quality combination with the GLP rules will be the way that the laboratories will tend to select more in the next years.

References:

References World Health Organisation ,For Research On Diseases of poverty, Good Laboratory Practices http://www.labcompliance.com/tutorial/glp/default.aspx?sm=d_a http://www.sjsu.edu/faculty/chem55/55glpout.htm Wikipedia

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