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S.SusenaPharmaceutical analysis &QASSJ COLLEGE OF PHARMACY,HYDERABAD
INTRODUCTION TO GLP WHY WAS GLP CREATED?? NEED OF NON-CLINICAL TESTING?? GLP & USFDA.. USFDA GUIDELINES OF GLP FOR NON-CLINICAL TRAILS….
GLP is an FDA regulation. It is defined in OECD principles as ―a qualitysystem concerned with organisationalprocess and the conditions under whichnon-clinical health and environmentalsafety studies are planned,performed,monitored,recorded,archived and reported.
GLP is a formal regulation that was created by the FDA(United states food and drug administration) in 1978. Although GLP originated in the United States , it had a worldwide impact. Non-US companies that wanted to do business with theUnited states or register their pharmacies in the United Stateshad to comply with the United States GLP regulations. They eventually started making GLP regulations in their homecountries. In 1981 an organization named OECD (organization foreconomic co-operation and development ) produced GLPprinciples that are international standard.
In the early 70’s FDA becameaware of cases of ( PLP ) poorlaboratory practice all over theUnited States. FDA decided to do an in-depthinvestigation in 40 toxicologylabs.They discovered a lot fraudulentactivities and a lot of poor labpractices.Examples of some of these ( PLP )poor lab practices found were Equipment not been calibratedto standard form , thereforegiving wrong measurements. Incorrect/inaccurate accounts ofthe actual lab study
One of the labs that wentunder such an investigationmade headline news. The name of the Lab wasIndustrial Bio Test. This was abig lab that ran tests for bigcompanies such as Procter andGamble. It was discovered that micethat they had used to testlotion and deodorants haddeveloped cancer and died
To promote the development ofquality test data.. Set standards for ensuring thequality,reliability & integrity ofstudies... To ensure good operationalmanagement… Focus on aspects of studyexecution(planning,monitoring,recording, reporting, archiving).
DEFINATION: (NON-CLINICAL LABORATORY STUDY)Non-clinical laboratory study means in vivo/in vitroexperiments in which test articles are studiedprospectively in test systems to determine theirsafety.Donot include –studies utilizing humansubjects/animal trails.
Characterisation of toxic effects with respect totarget organs. Dose dependence To estimate an initial safe starting dose & doserange for human trials To identify parameters for clinical monitoring tocharacterise potential adverse effects that mightoccur during clinical trial
The united states FDA has rulesfor GLP in 21CFR58. Non-clinical trials use these rulesprior to clinical research inhumans. Research not conducted underthese restrictions or researchdone outside US not conductedaccordingly to the FDA rulesmight be inadmissible in supportof NDA in US.
[code of Federal Regulations][Title 21, volume 1][CITE:21CFR58]TITLE 21—FOOD AND DRUGSCHAPTER 1—FOOD AND DRUG ADMINISTRATIONDEPARTMENT OF HEALTH AND HUMAN SERVICESSUB CHAPTER A-- GENERAL21 CFR PART 58:GOOD LABORATORY PRACTICES (GLP) FOR NON-CLINICALLABORATORY STUDIES.
Subpart A: General ProvisionsSubpart B: Organization and PersonnelSubpart C: FacilitiesSubpart D: EquipmentSubpart E: Testing Facilities OperationSubpart F: Test and Control ArticlesSubpart G: Protocol for and Conduct of aNon-Clinical Laboratory StudySubpart J: Records and ReportsSubpart K: Disqualification of TestingFacilities
Sec58.1:SCOPESec58.3:DEFINATIONSSec58.10:APPLICABILITY TO STUDIES PERFORMEDUNDER GRANTS & CONTRACTSSec58.15:INSPECTION OF A TESTING FACILITY
This part includes good laboratory practices forconducting non-clinical laboratory studies that support/intended to support applications for research ormarketing permits for products regulated by FDAincludingfood and colour additives,animal food additives,human and animal drugs,medical devices for human use,biological products and electronic products. Compilance with this part is intended to assure thequality and integrity of the safety data filed undersections of Food,Drug and Cosmetics Act.
a) Actb) Test articlec) Control articled) Non-clinical laboratory studye) Application for research or marketing permit
Sec. 58.10 Applicability to studies performed undergrants and contracts When a sponsor conducting a nonclinicallaboratory study intended to be submitted to orreviewed by the FDA utilizes the services of aconsulting laboratory, contractor, or grantee toperform an analysis or other service, it shallnotify the consulting laboratory, contractor, orgrantee that the service is part of a nonclinicallaboratory study that must be conducted incompliance with the provisions of this part.16
Sec. 58.15 Inspection of a testingfacilityA testing facility shall permit an authorizedemployee of the FDA, at reasonable times and in areasonable manner, to inspect the facility and toinspect all records and specimens required to bemaintained regarding studies within the scope ofthis part.The records inspection and copying requirementsshall not apply to quality assurance unit records offindings and problems, or to actions recommendedand taken.The FDA will not consider a nonclinical laboratorystudy in support of an application for a research ormarketing permit if the testing facility refuses topermit inspection.17
58.29 PersonnelEvery individual in testing facilityShould have education,training,expirence. Maintain current summary of job , Shall be sufficient in number, Shall take neccesary personal sanitation,healthprecautions to avoid contamination of testsystems. Shall clearly understand the functions they areto perform.18
58.33 Study Director 58.35 Quality Assurance Unit ―A scientist /proffesional ofappropriateeducation,training,experience‖ Responsible for overalltechnical conduct of thestudy,Interpretation,analysis,documentation &reporting of results. Single point of study control. ―A independent personalresponsible to assure themanagement(I,e-facilities,equipment, personnel,methods,practices,recordsand controls are inconformance with theregulations in that part.‖19
FACILITIES…58.41 General―Each testing facility shall be of suitable size andconstruction to facilitate the proper conduct ofnonclinical laboratory studies. It shall be designedso that there is a degree of separation that willprevent any function or activity from having anadverse effect on the study.‖ Animal care facilities Animal supply facilities Facilities for handling test and control articles Laboratory operation areas Specimen and data storage facilities20
EQUIPMENT…58.61 Equipment Design―Equipment used in ... shall be of appropriatedesign and adequate capacity ...‖58.63 Maintenance and Calibration(a) ―The written standard operating procedures ...‖(b) ―Written records shall be maintained ...‖ Log book Not for GLP use.21
23Sec 58.81: STANDARD OPERATINGPROCEDURES:(a) A testing facility shall have standardoperating procedures in writing settingforth study methods that management issatisfied are adequate to insure thequality and integrity of the data generatedin the course of a study.‖ Written procedures for a laboratoriesprogram. They define how to carry out protocol-specified activities. Most often written in a chronologicallisting of action steps. They are written to explain how theprocedures are suppose to work.SUBPART E- FACILITIES TESTING OPERATION:
24 SOPs should accurately reflect howroutine tasks are performed Routine inspection, cleaning,maintenance, testing andcalibration. Actions to be taken in response toequipment failure. Reviewed on regular basis.
There should be SOP’s for housing, feeding,handling and caring of animals. Diagnosis, authorizations of treatment oftreatment, description of treatment, each date oftreatment shall be documented & retained.REAGENTS and SOLUTIONS: Reagents and solutions in laboratory areas shall belabelled to indicate identity, titer or concentrations,storage requirements and expiration date.
Test and control article characterisation: the identity , strength, purity and composition or othercharacteristics which will define the test or control articlesshall be determined for each batch & documented. Method of synthesis, fabrication, derivation of the articlesshall be documented by sponsor /testing facility. Procedures shall be established for proper handling. Distribution is made in a designed manner to preventpossibility of contamination,deteriotation and damage.
SUBPART G- PROTOCOL FOR ANDCONDUCT OF A NON-CLINICALLABORATORY STUDY:58.120 Protocol―Each study shall have an approved written protocol that clearlyindicates the objectives and all methods for the conduct of thestudy.‖58.130 Conduct of a Non-clinical Laboratory Study―The nonclinical laboratory study shall be conducted in accordance withthe protocol‖27
58.185 Reporting of Non-clinical Laboratory StudyResults―A final report shall be prepared for each nonclinicallaboratory study Which include a detailed documentation ofhow whole study carried out by the testing facility ...‖58.190 Storage and Retrieval of Records and Data―All raw data, documentation, protocols, final reports, andspecimens ... Generated as a result of the study shall beretained and shall be orderly stored in archives.‖
Grounds of disqualification:The commissioner may disqualify a testing facilityupon finding: The testing facility failed to comply with one ormore of the regulations. Non-compliance adversely affected the validity ofthe non-clinical laboratory study.
31The FDA states the followingconsequences of noncompliance: The commissioner will send a writtenproposal of disqualification to the testingfacility A regulatory hearing on the disqualificationwill be scheduled If the commissioner finds that after thehearing, the facility has complied, then awritten statement with an explanation oftermination of disqualification will be sentto the facility Thus, if it can be shown that suchdisqualifications did not affect the integrityand outcome of the study itself, or did not
32If the commissioner finds that the facility showed anoncompliance, any of the grounds after the hearing, thena final order of noncompliance will be sent to the facilitywith explanations If a testing facility has been disqualified, any studies donebefore of after the disqualification will need to be determinedas essential to a decision (acceptable or not) If the study is determined unacceptable, then the facilityitself may need to show that the study was not affected bythe noncompliance that led to the disqualification Once finally disqualified, the facility may not receive or beconsidered for a research or marketing permit and the studyis rejected.
33 The commissioner may notify the public and all interestedpersons, including other federal agencies the facility mayhave contacted The FDA may ask the other agencies to consider whether tosupport the facility or not under the disqualification Civil or criminal proceedings may occur at the discretion ofthe commissioner Fines of up to $50,000 if one knowingly commits crimeand/or 1 year imprisonment~ for registration applicantsand producers Fines up to $5,000 all others~ civil penalty after failing toimprove after a minor violation warning was issued~ onlythose involved in testing will be given civil penalties Those involved in the distribution or sales will be assessedmore heavy penalties, such as criminal penalties
34 The FDA may turn it over to the federal, state or locallaw enforcement The facility’s sponsor may terminate or suspend thefacility from doing any non- clinical study for a permit The sponsor is required to notify the FDA in writingwithin 15 working days that the facility is to besuspended or terminated and why
35 The commissioner will inspect the facility anddetermine if it shall be reinstated If it is reinstated, the commissioner is required tonotify all persons that were notified of thedisqualification including the facility itself
These Regulations specify minimum standards for theconduct of safety testing to achieve great results withminimal adverse effects. The Principles may be considered as a set of criteria to besatisfied as a basis for ensuring the quality, reliability andintegrity of studies, the reporting of verifiable conclusions,and the traceability of data.
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 forregulated non-clinical research and development -2nd ed., WHOLibrary Cataloguing-in-Publication Data, 2nd ed., 7,15-20OECDPrinciples 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_2649_34381_2346175_1_1_1_37465,00.html. Schneider, K (1983(Spring)). "Faking it: The case againstIndustrial Bio-Test Laboratories". Amicus Journal (NaturalResources Defence Council): 14-26.