Good Good Laboratory Laboratory Practice Practice This workforce solution was funded by a grant awarded under the President’s Community-Based Job Training Grants as implemented by the U.S. Department of Labor’s Employment and Training Administration. The solution was created by the grantee and does not necessarily reflect the official position of the U.S. Department of Labor. The Department of Labor makes no guarantees, warranties, or assurances of any kind, express or implied, with respect to such information, including any information on linked sites and including, but not limited to, accuracy of the information or its completeness, timeliness, usefulness, adequacy, continued availability, or ownership. This solution is copyrighted by the institution that created it. Internal use by an organization and/or personal use by an individual for non-commercial purposes is permissible. All other uses require the prior authorization of the copyright owner.
Transcript
Good Laboratory Good Laboratory Practice Practice
This workforce solution was funded by a grant awarded under the President’s Community-Based Job Training Grants as implemented by the U.S. Department of Labor’s Employment and Training Administration. The solution was created by the grantee and does not necessarily reflect the official position of the U.S. Department of Labor. The Department of Labor makes no guarantees, warranties, or assurances of any kind, express or implied, with respect to such information, including any information on linked sites and including, but not limited to, accuracy of the information or its completeness, timeliness, usefulness, adequacy, continued availability, or ownership. This solution is copyrighted by the institution that created it. Internal use by an organization and/or personal use by an individual for non-commercial purposes is permissible. All other uses require the prior authorization of the copyright owner.
OverviewOverview
History of RegulationsHistory of Regulations GLP RegulationsGLP Regulations
ObjectivesObjectives
Participants will learnParticipants will learn The history behind GLPs and other regulationsThe history behind GLPs and other regulations The basic GLP terminologyThe basic GLP terminology The similarities and differences between various The similarities and differences between various
agency regulationsagency regulations
REGULATIONS ARE NOT NEW
Ancient Egyptians and Hebrews Meat handling laws
Greeks and Romans Regulations prohibiting the addition ofwater to wine
England - Magna Carta (1215) Established a standard system of weights
Middle Ages-apothecaries and Prohibited adulteration of drugs andgrocers organized trade guilds spices (by self-inspection)
Massachusetts Bay Colony (1646) Regulations standardized the size ofa loaf of bread
Massachusetts Bread Law (1720) Prohibited substitution of other grainsin bread (limited adulteration)
Massachusetts "Act against selling First comprehensive foodunwholesome provisions" (1785) adulteration law in the United States
After the American Revolution, States continued to pass food laws which usually reflected their specialized local interests, but drug laws were strikingly absent ...
• Grossed $75 million annually
• More alcohol consumed in patent medicines than sold in liquor stores
• Biggest advertisers in newspapers
• Sold by touring medicine shows
• Endorsements and testimonials that claimed “miracle cures””
Patent Medicine Industry
The formula for “Peruna”, a popular remedy, was published. It contained the following ingredients:
• 1/2 pint of 90% proof spirits
• 1 1/2 pints of water
• a flavor cube
• a little burned sugar for color
Patent Medicine IndustryPatent Medicine Industry
Early 1900sEarly 1900s 19011901- Serious diphtheria - Serious diphtheria
epidemicepidemic 10 children died after 10 children died after
being treated with being treated with antitoxin produced by city antitoxin produced by city of St. Louisof St. Louis
Antitoxin was Antitoxin was contaminated with contaminated with tetanus-horse from which tetanus-horse from which antitoxin obtained had antitoxin obtained had tetanustetanus
No safety testing No safety testing performed on productperformed on product
Early 1900sEarly 1900s 19021902- Biologics Control Act passed- Biologics Control Act passed
Ensure purity and safety of serums, vaccines, and Ensure purity and safety of serums, vaccines, and similar productssimilar products
Required licensing of manufacturing establishments Required licensing of manufacturing establishments and manufacturersand manufacturers
Provided inspection authority to the federal Provided inspection authority to the federal governmentgovernment
19031903 – Federal authorities issued first biologics regulations – Federal authorities issued first biologics regulations Administered by the Public Health Service’s Administered by the Public Health Service’s
Hygienic LaboratoryHygienic Laboratory Required annual renewal of establishment licensesRequired annual renewal of establishment licenses Formalized the concept of unannounced Formalized the concept of unannounced
government inspectionsgovernment inspections
Early 1900sEarly 1900s 19061906 - Food and Drugs Act - Food and Drugs Act
commerce in misbranded commerce in misbranded and adulterated foods, and adulterated foods, drinks, and drugsdrinks, and drugs
19061906 – Meat Inspection Act – Meat Inspection Act passed same daypassed same day
Early 1900sEarly 1900s 19111911- U.S. v. Johnson rules - U.S. v. Johnson rules
that the 1906 Act does not that the 1906 Act does not prohibit false therapeutic prohibit false therapeutic claimsclaims
19121912- Sherley Amendment - Sherley Amendment prohibits labeling prohibits labeling medicines with false medicines with false therapeutic claims intended therapeutic claims intended to defraud the purchaserto defraud the purchaser
19241924- U.S. v. 95 Barrels - U.S. v. 95 Barrels Alleged Apple Cider Alleged Apple Cider Vinegar rules that the Vinegar rules that the 1906 Act condemns 1906 Act condemns every statement , every statement , design, or device on a design, or device on a product’s label that may product’s label that may mislead or deceive even mislead or deceive even if technically trueif technically true
Early 1900sEarly 1900s
19301930- Ransdell Act redesignated the federal - Ransdell Act redesignated the federal government’s Hygienic Laboratory as the National government’s Hygienic Laboratory as the National Institutes of Health (NIH) which began funding Institutes of Health (NIH) which began funding research in 1935research in 1935
19321932- The Tuskegee Study, a large prospective - The Tuskegee Study, a large prospective ‘natural history’ study of untreated latent syphilis in ‘natural history’ study of untreated latent syphilis in 400 poor black men, funded by the Public Health 400 poor black men, funded by the Public Health Service, was begunService, was begun
Early 1900sEarly 1900s
19331933- FDA recommends a complete revision - FDA recommends a complete revision of the 1906 Food and Drugs Actof the 1906 Food and Drugs Act Bill goes before Senate, beginning a five-year Bill goes before Senate, beginning a five-year
legislative battlelegislative battle 19371937- Elixir of Sulfanilamide- Elixir of Sulfanilamide
Contained diethylene glycol as a vehicleContained diethylene glycol as a vehicle Killed 107 peopleKilled 107 people
Early 1900sEarly 1900s 19381938- Federal Food, Drug, and Cosmetic (FDC) - Federal Food, Drug, and Cosmetic (FDC)
Act passed by CongressAct passed by Congress Extended control to cosmetics and Extended control to cosmetics and
therapeutic devicestherapeutic devices Required new drugs to be tested for safety Required new drugs to be tested for safety
before marketing, the results of which before marketing, the results of which would be submitted to FDA in a new drug would be submitted to FDA in a new drug application (NDA)application (NDA)
Eliminated the Sherley Amendment Eliminated the Sherley Amendment requirement to prove intent to defraudrequirement to prove intent to defraud
Required drugs have adequate labeling for Required drugs have adequate labeling for safe usesafe use
Early 1900sEarly 1900s 19381938- Federal Food, Drug, and Cosmetic (FDC) - Federal Food, Drug, and Cosmetic (FDC)
Act passed by Congress (continued)Act passed by Congress (continued) Authorized standards of identity, quality, Authorized standards of identity, quality,
and fill-of-container for foodsand fill-of-container for foods Authorized factory inspectionsAuthorized factory inspections Added the remedy of court injunctions to Added the remedy of court injunctions to
the previous penalties of seizures and the previous penalties of seizures and prosecutionsprosecutions
Requests for efficacy standard not adopted; Requests for efficacy standard not adopted; a standing request of the FDA since 1933a standing request of the FDA since 1933
Mid 1900sMid 1900s
19411941- Sulfathiazole tablets tainted with the sedative - Sulfathiazole tablets tainted with the sedative phenobarbitalphenobarbital Nearly 300 deaths and injuries result from the Nearly 300 deaths and injuries result from the
distribution of these tabletsdistribution of these tablets Prompted the FDA to revise manufacturing and Prompted the FDA to revise manufacturing and
quality controls, the beginning of what would later quality controls, the beginning of what would later be called good manufacturing practices (GMPs)be called good manufacturing practices (GMPs)
Mid 1900sMid 1900s 19431943- U.S. v. Dotterweich - U.S. v. Dotterweich
Supreme Court ruled the responsible Supreme Court ruled the responsible officials of a corporation and the officials of a corporation and the corporation itself may be prosecuted for corporation itself may be prosecuted for violationsviolations
Did not need to be proven that the officials Did not need to be proven that the officials knew of or intended the violationsknew of or intended the violations
19441944- Public Health Service Act passed, included - Public Health Service Act passed, included regulation of biological productsregulation of biological products
Mid 1900sMid 1900s
19471947- Nuremberg Code drafted- Nuremberg Code drafted 10 point code that described the basic principles of 10 point code that described the basic principles of
ethical behavior in the conduct of human ethical behavior in the conduct of human experimentationexperimentation
Three pivotal points were stressed:Three pivotal points were stressed: Voluntary consent of the subject must be Voluntary consent of the subject must be
obtainedobtained Prior animal experimentation to determine risk Prior animal experimentation to determine risk
must be performedmust be performed Human experimentation must be performed by Human experimentation must be performed by
qualified medical personnelqualified medical personnel
Mid 1900sMid 1900s 19511951- Durham-- Durham-
Humphrey Humphrey Amendment defined Amendment defined the kinds of drugs the kinds of drugs that cannot be used that cannot be used without medical without medical supervision and supervision and limited their sale to limited their sale to prescription by prescription by licensed professionalslicensed professionals
authority updated authority updated and clarifiedand clarified
Established the legal Established the legal foundation for the foundation for the FDA 483 being issued FDA 483 being issued at close of inspectionsat close of inspections
Removed the need for Removed the need for FDA to obtain FDA to obtain consent before consent before inspectionsinspections
Required manufacturers of new food Required manufacturers of new food additives to establish safetyadditives to establish safety
Prohibited the approval of any food Prohibited the approval of any food additive shown to induce cancer in humans additive shown to induce cancer in humans or animalsor animals
19601960- Color Additive Amendment- Color Additive Amendment Required manufacturers to establish safety Required manufacturers to establish safety
of color additives in foods, drugs, and of color additives in foods, drugs, and cosmeticscosmetics
Prohibited the approval of any color Prohibited the approval of any color additive shown to induce cancer in humans additive shown to induce cancer in humans or animalsor animals
New sleeping pill, caused birth defects in thousands New sleeping pill, caused birth defects in thousands of babies in Europeof babies in Europe
Dr. Frances Kelsey refused to allow the NDA to Dr. Frances Kelsey refused to allow the NDA to become effective in the US because of insufficient become effective in the US because of insufficient safety datasafety data
19621962- Kefauver-Harris Drug Amendments- Kefauver-Harris Drug Amendments Required drug manufacturers for the first time to Required drug manufacturers for the first time to
prove to the FDA the effectiveness of their products prove to the FDA the effectiveness of their products before marketingbefore marketing
Addressed safety requirements for testing on human Addressed safety requirements for testing on human subjectssubjects
Mid 1900sMid 1900s 19621962- Kefauver-Harris Drug Amendments (continued)- Kefauver-Harris Drug Amendments (continued)
Required that patients be informed if they are Required that patients be informed if they are taking a drug that is experimentaltaking a drug that is experimental
Required drug companies to report to the FDA any Required drug companies to report to the FDA any adverse effects found in clinical trials of drugs adverse effects found in clinical trials of drugs
Required the drug label to carry the common or Required the drug label to carry the common or generic name as well as the brand namegeneric name as well as the brand name
Required that prescription drug advertising to Required that prescription drug advertising to doctors list the side effects as well as benefits of the doctors list the side effects as well as benefits of the drugdrug
Mid 1900sMid 1900s
19631963- Overseas thalidomide catastrophe was instrumental in - Overseas thalidomide catastrophe was instrumental in the FDA completing the first draft of Good Manufacturing the FDA completing the first draft of Good Manufacturing Practices (GMPs) and making them legal requirements. GMPs Practices (GMPs) and making them legal requirements. GMPs set requirements for sanitation, inspection of materials and set requirements for sanitation, inspection of materials and finished products, record-keeping, and other quality controlsfinished products, record-keeping, and other quality controls
Mid 1900sMid 1900s 19641964- the 18- the 18th th World Medical Assembly adopted a World Medical Assembly adopted a
resolution on human experimentation called The resolution on human experimentation called The Declaration of HelsinkiDeclaration of Helsinki Outlined the basic principles of human experimentationOutlined the basic principles of human experimentation Required informed consent of study subjectsRequired informed consent of study subjects Described compliance measures relating to ethical Described compliance measures relating to ethical
approval and review of researchapproval and review of research
Mid 1900sMid 1900s 19661966
Dr. Harry Beecher exposed ongoing unethical Dr. Harry Beecher exposed ongoing unethical experimentation on human subjects in his article experimentation on human subjects in his article “Ethics and Clinical Research” published in the “Ethics and Clinical Research” published in the New England Journal of Medicine. This paper New England Journal of Medicine. This paper described 22 ongoing trials that failed to meet described 22 ongoing trials that failed to meet standards in the Nuremberg Code and the standards in the Nuremberg Code and the Declaration of HelsinkiDeclaration of Helsinki
Formal statement issued by the Surgeon General Formal statement issued by the Surgeon General mandating peer review by a committee of mandating peer review by a committee of investigator’s institutional associates and informed investigator’s institutional associates and informed consent for all PHS funded researchconsent for all PHS funded research
1970 to Today1970 to Today
19701970 In In Upjohn v. FinchUpjohn v. Finch, the Court of Appeals upheld the , the Court of Appeals upheld the
1962 efficacy amendment by ruling that commercial 1962 efficacy amendment by ruling that commercial success alone does not constitute substantial success alone does not constitute substantial evidence of drug safety and efficacyevidence of drug safety and efficacy
FDA required the first Patient Package Insert FDA required the first Patient Package Insert containing information about specific risks and containing information about specific risks and benefits in oral contraceptivesbenefits in oral contraceptives
EPA established and takes over FDA program for EPA established and takes over FDA program for pesticide tolerancespesticide tolerances
1970 to Today1970 to Today
19711971- PHS Bureau of - PHS Bureau of Radiological Health Radiological Health transferred to FDAtransferred to FDA
19721972- Regulation of - Regulation of Biologics (serums, vaccines, Biologics (serums, vaccines, and blood products) is and blood products) is transferred from NIH to transferred from NIH to FDAFDA
1970 to Today1970 to Today
19731973- New Zealand formally passed the Testing Laboratory - New Zealand formally passed the Testing Laboratory Registration ActRegistration Act First country to formally address a government First country to formally address a government
policy of ‘good laboratory practices’policy of ‘good laboratory practices’ Defined ‘the testing laboratory’ to include staff Defined ‘the testing laboratory’ to include staff
records, equipment, procedures, and facilitiesrecords, equipment, procedures, and facilities Established a testing laboratory registration council Established a testing laboratory registration council
to ‘promote the development and maintenance of to ‘promote the development and maintenance of good laboratory practice in testing’good laboratory practice in testing’
1970 to Today1970 to Today
19741974- The National Research Act passed- The National Research Act passed Revelations of the Tuskegee Study in 1972 were largely responsible Revelations of the Tuskegee Study in 1972 were largely responsible
for its passagefor its passage Set up a commission to define ethical standards under which Set up a commission to define ethical standards under which
research in the United States was to be conductedresearch in the United States was to be conducted Established federal law requiring the review of all clinical research Established federal law requiring the review of all clinical research
by an Institutional Review Board (IRB)by an Institutional Review Board (IRB)
1970 to Today1970 to Today
19751975- During Senate subcommittee on health meeting, - During Senate subcommittee on health meeting, allegations brought against Searle laboratories by FDA allegations brought against Searle laboratories by FDA employees re: conducting and reporting animal safety employees re: conducting and reporting animal safety standards. Searle agrees to co-operate fully while the FDA standards. Searle agrees to co-operate fully while the FDA undertook a thorough investigation of nonclinical research at undertook a thorough investigation of nonclinical research at Searle.Searle.
1970 to Today1970 to Today
19761976 Number of scientists at Searle developed a Number of scientists at Searle developed a
document entitled ‘Good Laboratory Practice’ document entitled ‘Good Laboratory Practice’ which was submitted to the FDA and PMAwhich was submitted to the FDA and PMA
Bioresearch Monitoring Program created within the Bioresearch Monitoring Program created within the FDAFDA
GMPs for blood and blood products created. The GMPs for blood and blood products created. The catalyst- question of sterility on large volume catalyst- question of sterility on large volume parenteralsparenterals
Conducted studies for the federal government, Conducted studies for the federal government, as well as for private companiesas well as for private companies
Performed 35% to 40% of all U.S. toxicology Performed 35% to 40% of all U.S. toxicology teststests
Numerous discrepancies in study conduct and Numerous discrepancies in study conduct and datadata
The Case Against IBTThe Case Against IBT An employee of Syntex Corp. notified the An employee of Syntex Corp. notified the
FDA of problemsFDA of problems Naprosyn, an antiarthritic drug tested by Naprosyn, an antiarthritic drug tested by
IBT IBT Syntex employee expressed concern to IBT Syntex employee expressed concern to IBT
officials about submitted reportofficials about submitted report The file provided enough evidence to warrant The file provided enough evidence to warrant
an inspection of the facility by the FDAan inspection of the facility by the FDA
The Case Against IBTThe Case Against IBT
The SwampThe Swamp Mortality rate reached 80%Mortality rate reached 80% Faulty nozzles on automatic watering system Faulty nozzles on automatic watering system
created a chilling mist created a chilling mist Escaped rats were not recovered, thus creating a Escaped rats were not recovered, thus creating a
wild breeding stock on the floorwild breeding stock on the floor TBD- “too badly decomposed”TBD- “too badly decomposed”
The Case Against IBTThe Case Against IBT 1976- FDA uncovers IBT fraud1976- FDA uncovers IBT fraud
Section Head for Rat Toxicology, submitted fraudulent mortality Section Head for Rat Toxicology, submitted fraudulent mortality datadata
1000 new mice ordered to replace those that had died during the 1000 new mice ordered to replace those that had died during the studystudy
Blood and urine analyses were fabricated at the end of a 2 year rat Blood and urine analyses were fabricated at the end of a 2 year rat studystudy
Management forged signatures on reportsManagement forged signatures on reports Indictments on 8 counts for conducting and distributing false Indictments on 8 counts for conducting and distributing false
scientific datascientific data
The Mark of IBTThe Mark of IBT
Over 22,000 studies to their creditOver 22,000 studies to their credit IBT studies were the basis for safe product rating for hundreds IBT studies were the basis for safe product rating for hundreds
of drugs and pesticidesof drugs and pesticides Of 1205 key pesticide studies, only 214 (18%) of the studies Of 1205 key pesticide studies, only 214 (18%) of the studies
were found to be valid after retestingwere found to be valid after retesting Of 867 agency audits, 618 (71%) of the studies were found to Of 867 agency audits, 618 (71%) of the studies were found to
be invalidbe invalid
1970 to Today1970 to Today 19761976 (continued) (continued)
Medical Device Amendment passed to ensure safety and Medical Device Amendment passed to ensure safety and effectiveness of medical devices, including diagnostic productseffectiveness of medical devices, including diagnostic products
Required manufacturers to register with the FDA and follow Required manufacturers to register with the FDA and follow quality control proceduresquality control procedures
Some products are required to have premarket approval by the Some products are required to have premarket approval by the FDA; others must meet performance standards before FDA; others must meet performance standards before marketingmarketing
1970 to Today1970 to Today 19771977- Clinical Inspection - Clinical Inspection
Program incorporated into Program incorporated into Bioresearch Monitoring Bioresearch Monitoring Program Program
19781978-- GLP regulations are GLP regulations are
finalizedfinalized GMP regulations for GMP regulations for
drugs/finished drugs/finished pharmaceuticals are pharmaceuticals are finalized and finalized and effectiveeffective
1970 to Today1970 to Today 19791979
FDA GLPs became effectiveFDA GLPs became effective Recommendations of the commission set up by the Recommendations of the commission set up by the
National Research Act printed in the Federal National Research Act printed in the Federal Register as The Belmont Report. It described the Register as The Belmont Report. It described the three basic principles of medical research on human three basic principles of medical research on human subjectssubjects
Autonomy/Respect for PersonsAutonomy/Respect for Persons BeneficenceBeneficence JusticeJustice
1970 to Today1970 to Today 19801980- EPA GLPs proposed- EPA GLPs proposed 19811981--
Regulation on informed Regulation on informed consent of clinical consent of clinical subjects is finalizedsubjects is finalized
Regulation on the Regulation on the responsibilities of responsibilities of Institutional Review Institutional Review Boards (IRBs) is finalizedBoards (IRBs) is finalized
19831983- - EPA GLPs finalizedEPA GLPs finalized Orphan Drug Act Orphan Drug Act
passed enabling the passed enabling the FDA to promote FDA to promote research and research and marketing of drugs marketing of drugs needed for rare needed for rare diseasesdiseases
1970 to Today1970 to Today
19871987 Investigational Drug regulations revised to expand Investigational Drug regulations revised to expand
access to experimental drugs for patients with access to experimental drugs for patients with serious diseases with no alternative therapiesserious diseases with no alternative therapies
FDA revised regulations (IND Rewrite) in an effort FDA revised regulations (IND Rewrite) in an effort to facilitate the drug approval process by clearly to facilitate the drug approval process by clearly defining the objectives of different phases and how defining the objectives of different phases and how these phases are regulatedthese phases are regulated
FDA/EPA GLPs amendedFDA/EPA GLPs amended
1970 to Today1970 to Today
19891989- Global standards for clinical research were - Global standards for clinical research were established by the International Conference on established by the International Conference on Harmonization (ICH)Harmonization (ICH)
19901990- Safe Medical Devices Act passed- Safe Medical Devices Act passed Required facilities that use medical devices to Required facilities that use medical devices to
report to the FDA incidents that suggest a medical report to the FDA incidents that suggest a medical device caused death, serious injury or illness to a device caused death, serious injury or illness to a patientpatient
Manufacturers are required to conduct post-Manufacturers are required to conduct post-market surveys on permanently implanted devicesmarket surveys on permanently implanted devices
Authorized FDA to order device product recallsAuthorized FDA to order device product recalls
1970 to Today1970 to Today 19921992- Prescription Drug User Fee Act- Prescription Drug User Fee Act
Required drug and biologics manufacturers to pay Required drug and biologics manufacturers to pay fees for product applicationsfees for product applications
Required FDA to use these funds to hire more Required FDA to use these funds to hire more reviewers to assess these applicationsreviewers to assess these applications
19971997- Electronic Records and Signatures Rule provided - Electronic Records and Signatures Rule provided criteria under which FDA will consider electronic records criteria under which FDA will consider electronic records equivalent to paper records and electronic signatures equivalent to paper records and electronic signatures equivalent to handwritten signaturesequivalent to handwritten signatures
1970 to Today1970 to Today
19971997- Food and Drug Administration Modernization Act- Food and Drug Administration Modernization Act Reauthorized PDUFA of 1992Reauthorized PDUFA of 1992 Provided measures to accelerate review of devicesProvided measures to accelerate review of devices Allowed expedited approval of fast track drugsAllowed expedited approval of fast track drugs Allowed FDA to request pediatric studies if the drug Allowed FDA to request pediatric studies if the drug
could potentially benefit childrencould potentially benefit children Regulated advertising of unapproved uses of Regulated advertising of unapproved uses of
approved drugs and devicesapproved drugs and devices
Pre-GLP PracticesPre-GLP Practices
Poorly done experimentsPoorly done experiments Uninformed personnelUninformed personnel Lack of supervisionLack of supervision Inadequate protocolsInadequate protocols Lack of documentationLack of documentation Poor animal carePoor animal care Inadequate sponsor monitoringInadequate sponsor monitoring Lack of Quality AssuranceLack of Quality Assurance
Why GLPs Why GLPs ?? Problems at laboratories such as IBT, and many Problems at laboratories such as IBT, and many
other laboratories prompted the need for a set of other laboratories prompted the need for a set of industry guidelinesindustry guidelines
Searle wrote the document entitled “Good Searle wrote the document entitled “Good Laboratory Practices”Laboratory Practices”
Though intended to be guidelines, the problems Though intended to be guidelines, the problems with IBT forced the FDA to enact the GLPs as lawwith IBT forced the FDA to enact the GLPs as law
United States GLP TimelineUnited States GLP Timeline
19001910
19201930
19401950
19601970
19801990
2000
Pure Food & Drugs Act Federal
Insecticide Act
Food Drug & Cosmetic Act
FIFRA
EPA Est.
FDA GLPs Final
EPA GLPs Final
Int’l Harmonization
RegulationsRegulations FDA 1978 FinalFDA 1978 Final
Food and Drug AdministrationFood and Drug Administration OECD 1981 OECD 1981
Organisation for Economic Cooperation and Organisation for Economic Cooperation and DevelopmentDevelopment
MHLW 1982MHLW 1982 Ministry of Health Labor and WelfareMinistry of Health Labor and Welfare
Regulations (cont.)Regulations (cont.)
EPA-FIFRA 1983 EPA-FIFRA 1983 Federal Insecticide, Fungicide and Rodenticide ActFederal Insecticide, Fungicide and Rodenticide Act
EPA-TSCA 1983EPA-TSCA 1983 Toxic Substances Control ActToxic Substances Control Act
JMAFF 1984JMAFF 1984 Japanese Ministry of Agriculture, Fisheries, and Japanese Ministry of Agriculture, Fisheries, and
ForestryForestry
Intent of the GLPsIntent of the GLPs
Assure quality/integrity of dataAssure quality/integrity of data Allow for accurate reconstructionAllow for accurate reconstruction Assist with approval/manufacture of safe Assist with approval/manufacture of safe
productsproducts
Scope of GLPsScope of GLPs
GLPs apply to GLPs apply to All studies supporting application/permits for FDA, EPA, All studies supporting application/permits for FDA, EPA,
or international agenciesor international agencies
GLPs do not apply to GLPs do not apply to Basic exploratory studiesBasic exploratory studies Clinical studiesClinical studies Testing in support of manufacturingTesting in support of manufacturing
Scale-up
Preclinical Research Clinical Development NDA Review
12-24 months 6-9 months1 month 9-12 months
12-24 months
6-18 months
Phase II
Phase IV
Phase III
Animal Safety Testing
SubmitIND
Submit NDA NDA Approval
Discovery to MarketDiscovery to Market
Pharmacology and Pharmacokinetics
Phase I
FormulationSynthesis and Physical Characterization
IND - Investigational New Drug
NDA - New Drug Application
Question and AnswerQuestion and Answer
GLP VocabularyGLP Vocabulary
GLP VocabularyGLP Vocabulary
Test article/substanceTest article/substance Control article/substanceControl article/substance CarrierCarrier Reference substanceReference substance StudyStudy SponsorSponsor Testing facilityTesting facility Test systemTest system
Raw dataRaw data Quality assuranceQuality assurance Study directorStudy director Study initiation dateStudy initiation date Study completion dateStudy completion date Experimental start dateExperimental start date Experimental termination dateExperimental termination date
Organization and PersonnelOrganization and Personnel
PersonnelPersonnel ManagementManagement Study DirectorStudy Director Quality Assurance UnitQuality Assurance Unit
PersonnelPersonnel Sufficient education, training, and/or experience Sufficient education, training, and/or experience Current summary of training and experienceCurrent summary of training and experience Sufficient number of personnelSufficient number of personnel Avoid contamination through personal sanitation and health Avoid contamination through personal sanitation and health
precautionsprecautions Wear appropriate clothingWear appropriate clothing Report any illness that may affect the studyReport any illness that may affect the study Have access to protocols and SOPsHave access to protocols and SOPs
Designate a Study Director and replace promptly if Designate a Study Director and replace promptly if necessarynecessary
Assure there is a Quality Assurance UnitAssure there is a Quality Assurance Unit Assure Test and Control Article CharacterizationAssure Test and Control Article Characterization Assure that personnel, resources, facilities, equipment, Assure that personnel, resources, facilities, equipment,
materials, and methodologies are available as scheduledmaterials, and methodologies are available as scheduled Assure that personnel clearly understand the functions they Assure that personnel clearly understand the functions they
are to performare to perform Assure that corrective actions are taken and documented as Assure that corrective actions are taken and documented as
a result of deviations noted by the QAUa result of deviations noted by the QAU
Test SiteTest Site Only defined by OECD and JMAFFOnly defined by OECD and JMAFF
The location(s) at which a phase of the study is conductedThe location(s) at which a phase of the study is conducted
Test Site ManagementTest Site Management Only defined by OECD and JMAFFOnly defined by OECD and JMAFF
The person(s) responsible for ensuring that the phase(s) of the The person(s) responsible for ensuring that the phase(s) of the study, for which he is responsible, are conducted according to these study, for which he is responsible, are conducted according to these Principles of GLPsPrinciples of GLPs
Study Director ResponsibilitiesStudy Director Responsibilities Has overall responsibility for studyHas overall responsibility for study
Is single point of study controlIs single point of study control
Must be available for questionsMust be available for questions
Study DirectorQAU
ReportPrep
Sponsor Management
SupportServices
Lab
PI
Principal InvestigatorPrincipal Investigator
Only defined by OECD and JMAFFOnly defined by OECD and JMAFF An individual who, for a multi-site study, acts on An individual who, for a multi-site study, acts on
behalf of the Study Director and has defined behalf of the Study Director and has defined responsibility for delegated phases of the study responsibility for delegated phases of the study
The Study Director’s responsibility for overall conduct The Study Director’s responsibility for overall conduct of the study of the study CANNOTCANNOT be delegated to the Principal be delegated to the Principal Investigator(s)Investigator(s)
Quality Assurance UnitQuality Assurance Unit The regulations mandate that a testing facility have a Quality The regulations mandate that a testing facility have a Quality
Assurance Unit in place to:Assurance Unit in place to: Monitor each study and report inspection resultsMonitor each study and report inspection results Assure management that facilities, equipment, personnel, methods, Assure management that facilities, equipment, personnel, methods,
practices, records, and controls conform to the GLPspractices, records, and controls conform to the GLPs Maintain a copy of the Master Schedule and SOPsMaintain a copy of the Master Schedule and SOPs Assure that no deviations from approved protocols or SOPs were Assure that no deviations from approved protocols or SOPs were
made without proper authorization and documentationmade without proper authorization and documentation
Quality Assurance Unit (cont.)Quality Assurance Unit (cont.) For any given study, the QAU must be entirely separate from and independent of the personnel engaged in the conduct and direction of that studyFor any given study, the QAU must be entirely separate from and independent of the personnel engaged in the conduct and direction of that study
FacilitiesFacilities Suitable size and constructionSuitable size and construction Separation of activitiesSeparation of activities
Test systemTest system Test system suppliesTest system supplies Test material handlingTest material handling Laboratory operationsLaboratory operations Specimen/data storageSpecimen/data storage Cleaning and SterilizingCleaning and Sterilizing
CleanlinessCleanliness
Common Facility DeficienciesCommon Facility Deficiencies
Pests Pests CleanlinessCleanliness Pesticide usePesticide use Unsuitable sizeUnsuitable size
EquipmentEquipment When is an instrument operating procedure needed?When is an instrument operating procedure needed?
Does it generate data?Does it generate data? Does it require special operating procedures?Does it require special operating procedures? Does it require calibration and maintenance?Does it require calibration and maintenance? Does it require cleanup to prevent contamination?Does it require cleanup to prevent contamination? Does it require safety procedures?Does it require safety procedures?
Require calibration to be traceable to national and international Require calibration to be traceable to national and international standards of measurementsstandards of measurements
Require validated computer systemsRequire validated computer systems
Common Equipment DeficienciesCommon Equipment Deficiencies
Failure to calibrateFailure to calibrate Failure to explain maintenance and repairsFailure to explain maintenance and repairs Failure to have SOPsFailure to have SOPs
Standard Operating ProceduresStandard Operating Procedures
Test system area preparationTest system area preparation Test system careTest system care Test and control materialsTest and control materials ObservationsObservations Laboratory testsLaboratory tests Test system handlingTest system handling Necropsy/postmortem examsNecropsy/postmortem exams
Deviations must be authorized by study Deviations must be authorized by study director and principal investigator director and principal investigator (if applicable)(if applicable)
Immediately available to personnelImmediately available to personnel
Common SOP DeficienciesCommon SOP Deficiencies
Not followedNot followed Don't existDon't exist Not currentNot current Not immediately available to staffNot immediately available to staff UnclearUnclear Unauthorized versions foundUnauthorized versions found
Animal Care (Test System)Animal Care (Test System)
Isolate newly received animalsIsolate newly received animals Individually identify animalsIndividually identify animals House different species in separate rooms House different species in separate rooms Physical/Chemical and Biological test systemsPhysical/Chemical and Biological test systems
Animal Care (Test System) Animal Care (Test System) cont’dcont’d
Animal equipment are to be cleaned and sanitizedAnimal equipment are to be cleaned and sanitized Analyze feed and water periodically for Analyze feed and water periodically for
contaminantscontaminants Bedding used is not to interfere with study, and is Bedding used is not to interfere with study, and is
to be kept dry and cleanto be kept dry and clean Pest control measures used are not to interfere with Pest control measures used are not to interfere with
study, and are to bestudy, and are to be documenteddocumented
Test and Control MaterialsTest and Control Materials
CharacterizationCharacterization HandlingHandling Mixing with carriersMixing with carriers
Characterization of Test and Characterization of Test and Control ArticlesControl Articles
Document identity, strength, purity, composition, etc. for Document identity, strength, purity, composition, etc. for each batcheach batch
Determine stability before study or concomitantly for each Determine stability before study or concomitantly for each test and control articletest and control article
Ensure proper labeling and storageEnsure proper labeling and storage Retain reserve samples for each batch/lot number for Retain reserve samples for each batch/lot number for
studies >4 weeks in durationstudies >4 weeks in duration
Handling of Test and Control Handling of Test and Control MaterialsMaterials
Need procedures for:Need procedures for: StorageStorage DistributionDistribution IdentificationIdentification Documentation of receipt/ distributionDocumentation of receipt/ distribution
Related ItemsRelated Items
Reference SubstancesReference Substances SolubilitySolubility Mixtures with Vehicle/CarriersMixtures with Vehicle/Carriers
Common Test Material Common Test Material DeficienciesDeficiencies
Unclear tracking (Chain of Custody)Unclear tracking (Chain of Custody) Required purity and stability testing not done Required purity and stability testing not done
and/ or not provided to study directorand/ or not provided to study director
Stability?
Common Reagent Labeling Common Reagent Labeling DeficienciesDeficiencies
Not properly labeledNot properly labeled ExpiredExpired Not properly storedNot properly stored
ProtocolProtocol Protocol clearly indicates the objectives and all methods for the conduct of the Protocol clearly indicates the objectives and all methods for the conduct of the
studystudy Cannot start a study without a sponsor approved SD signed protocolCannot start a study without a sponsor approved SD signed protocol Changes to the protocolChanges to the protocol Protocol tells you what to do, it does NOT stand as proof that you did it… Not Protocol tells you what to do, it does NOT stand as proof that you did it… Not
a substitute for raw dataa substitute for raw data Protocols always take precedence over SOPsProtocols always take precedence over SOPs
Common Protocol DeficienciesCommon Protocol Deficiencies
Not followedNot followed UnclearUnclear Untimely amendmentsUntimely amendments Amendment effective dates not documentedAmendment effective dates not documented Protocol not signed by Study director prior to Protocol not signed by Study director prior to
study conductstudy conduct
Why do we need to document?Why do we need to document?
Consider what would happen if we didn't...Consider what would happen if we didn't...
FDA’s reasons for data recordingFDA’s reasons for data recording GLP preamble states:GLP preamble states:
Consumer safety decisions based on dataConsumer safety decisions based on data Lab must ensure data quality and integrityLab must ensure data quality and integrity Documentation shows data quality and integrityDocumentation shows data quality and integrity
GLPs
Study ConductStudy Conduct Documentation Documentation
All data should be recorded directly, promptly, and legibly in inkAll data should be recorded directly, promptly, and legibly in ink All data should be signed or initialed and datedAll data should be signed or initialed and dated Changes must not obscure original entryChanges must not obscure original entry Changes in automated data should be made to indicate the reason Changes in automated data should be made to indicate the reason
for the change, dated, and the person making the change should be for the change, dated, and the person making the change should be identified identified
Project identification on all study documentsProject identification on all study documents Proper headings and unitsProper headings and units
Sign/initial and date all entries/pages.Sign/initial and date all entries/pages. Do not sign for work you did not do!Do not sign for work you did not do! If more than one person is responsible for the entries on a page, the data If more than one person is responsible for the entries on a page, the data
must indicate who was responsible for which entries.must indicate who was responsible for which entries. Sign/initial, date, and explain all corrections and changes.Sign/initial, date, and explain all corrections and changes. Never obliterate original entries. Never use White Out!Never obliterate original entries. Never use White Out!
Improper documentation is one of the most common citationsImproper documentation is one of the most common citations Proper documentation exampleProper documentation example
346 351 398 AK GR
3891
3/18/023/18/02
1 Recorded wrong number. Verified by reweighing. AK 3/18/02
Weighed byRecorded byBody Weights (g)
Electronic Signatures and DatesElectronic Signatures and Dates
Your electronic signature has the same legal Your electronic signature has the same legal ramification as your hand written signature.ramification as your hand written signature.
Example of Electronic Example of Electronic IdentificationIdentification
Usr2901
*******
Data Acquisition Login
Not an Electronic SignatureNot an Electronic Signature
Final ReportFinal Report
A final report shall be prepared for each nonclinical laboratory A final report shall be prepared for each nonclinical laboratory studystudy
The final report should reflect the data, methodologies, results The final report should reflect the data, methodologies, results and study director conclusionsand study director conclusions
Shall be signed and dated by the study director and appropriate Shall be signed and dated by the study director and appropriate personnelpersonnel
Report AmendmentReport Amendment
Common Final Report Common Final Report DeficienciesDeficiencies
Errors foundErrors found Lack of required compliance statementLack of required compliance statement Protocol deviations not reportedProtocol deviations not reported Final report not archivedFinal report not archived Final report not accurately reflecting raw dataFinal report not accurately reflecting raw data
Relationship Between Study Relationship Between Study RecordsRecords
Protocol- Says what we will doProtocol- Says what we will do Methods/SOPs- Says how we will do itMethods/SOPs- Says how we will do it Raw data- Says what we did and how we did itRaw data- Says what we did and how we did it The raw data prove we followed the protocol, methods, and The raw data prove we followed the protocol, methods, and
SOPsSOPs Final report- Reflects the raw data, and includes the study Final report- Reflects the raw data, and includes the study
director’s conclusions for the studydirector’s conclusions for the study
ArchivesArchives
One individual responsibleOne individual responsible Access for authorized personnel onlyAccess for authorized personnel only Archive material needs to be indexedArchive material needs to be indexed Expedient retrieval achievableExpedient retrieval achievable Conditions shall minimize deterioration of specimens and Conditions shall minimize deterioration of specimens and
datadata Timely archivalTimely archival
ArchivesArchives What gets archived?What gets archived?
– Raw dataRaw data– CorrespondenceCorrespondence– ProtocolProtocol– Final reportsFinal reports– SpecimensSpecimens– Supporting documentationSupporting documentation– Relevant facility information (e.g., temperature Relevant facility information (e.g., temperature
records, historical training files)records, historical training files)
Common Archiving DeficienciesCommon Archiving Deficiencies
Not timelyNot timely Incorrect indexingIncorrect indexing
Effects of NoncomplianceEffects of Noncompliance
If study is not GLP:If study is not GLP: Data may not be considered validData may not be considered valid
If the compliance statement is false:If the compliance statement is false: Loss of permitLoss of permit Forfeit of permit applicationForfeit of permit application Fines up to $25,000 per dayFines up to $25,000 per day Criminal prosecutionCriminal prosecution
ConclusionConclusion
The study director is the central point of control for a study.The study director is the central point of control for a study. All work has to be recorded directly, promptly, and legibly in All work has to be recorded directly, promptly, and legibly in
ink.ink. All raw data must be maintained! (even if recorded on the All raw data must be maintained! (even if recorded on the
following items: paper towel, sticky, or a glove.)following items: paper towel, sticky, or a glove.) All data must be signed and dated.All data must be signed and dated.
Conclusion (cont.)Conclusion (cont.)
Changes must not obscure original entry.Changes must not obscure original entry. Footnote, sign and date all correction changes.Footnote, sign and date all correction changes. Never obliterate original entries. NEVER USE WHITE OUT!Never obliterate original entries. NEVER USE WHITE OUT! All raw data generated during a study must be archived, when All raw data generated during a study must be archived, when
