glp training daniel w. sved, phd director, metabolism and analytical chemistry lori a. rush, bs,...
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GLP Training
Daniel W. Sved, PhD Director, Metabolism and Analytical Chemistry
Lori A. Rush, BS, LAT, RQAP-GLP Sponsor Specialist, Quality Assurance
Terms to Know
GLP Good Laboratory Practice
GMP Good Manufacturing Practice
GCPGood Clinical Practice
Terms to Know
Protocol A document which clearly indicates the
objectives and methods for the conduct of the study
SOP Standard operating procedure
Terms to Know
Electronic Record/Signature Regulations Part 11 (21 CFR Part 11)
CROMERR (40 CFR Part 3)
Definitions
Good Laboratory Practice Good Laboratory Practice (GLP) is a quality
system with the organizational process and the conditions under which non-clinical health and environmental safety studies are planned, performed, monitored, recorded, archived and reported.
ENV/MC/CHEM(98)17 2.1.1
Definitions
Master Schedule A compilation of information to assist in
the assessment of workload and for the tracking of studies at a test facility
ENV/MC/CHEM(98)17 2.2.10
Definitions
Nonclinical laboratory study In vivo or in vitro experiments in which test articles
are studied prospectively in test systems under laboratory conditions to determine their safety. The term does not include studies utilizing human subjects or clinical studies or field trials in animals. The term does not include basic exploratory studies carried out to determine whether a test article has any potential utility or to determine physical or chemical characteristics of a test article.
21 CFR Part 58.3(d)
Definitions
Sponsor A person who initiates and supports, by
provision of financial or other resources, a nonclinical laboratory study;
A person who submits a nonclinical study to the FDA in support of an application for a research or marketing permit; or
A testing facility, if it both initiates and actually conducts the study.
21 CFR Part 58.3(f)(1)(2)(3)
Definitions
Testing Facility A person who actually conducts a
nonclinical laboratory study, i.e., actually uses the test article in a test system.
21 CFR Part 58.3(g)
Definitions
Quality Assurance Unit Any person or organizational element,
except the study director, designated by testing facility management to perform the duties relating to quality assurance of nonclinical laboratory studies.
21 CFR Part 58.3(l)
Definitions
Standard Operating Procedures Documented procedures which describe
how to perform tests or activities normally not specified in detail in study plans or test guidelines
ENV/MC/CHEM(98)17 2.2.9
Definitions
Study Director The individual responsible for the overall
conduct of a nonclinical laboratory study.
21 CFR Part 58.3(m)
Definitions
Study initiation date The date the protocol is signed by the
study director Term defined in FDA, EPA FIFRA, EPA TSCA, OECD
GLPs
Definitions
Study completion date The date the final report is signed by the
study director Term defined in FDA, EPA FIFRA, EPA TSCA, OECD
GLPs
Definitions
Experimental start date The first date the test substance is
applied to the test system. Term defined in EPA FIFRA, EPA TSCA GLPs
Definitions
Experimental termination date The last date on which data are collected
directly from the study Term defined in EPA TSCA, EPA FIFRA GLPs
Experimental completion date The last date on which data are collected
from the study Term defined in OECD GLPs
Definitions
Experimental starting date The date on which the first study specific
data are collected. Term defined in OECD GLPs
What are GLPs?
GLPs are regulations that are intended to ensure the quality and integrity of the data in a nonclinical laboratory study.
GLPs are the LAW
They are NOT ideas
They are NOT governmental philosophy
They are NOT guidelines
Basic information
GLPs deal with: Planning Performance Monitoring Recording Reporting
GLPs do not: Attempt to
regulate science Ensure
“good science”
Basic information
Responsibility for establishing the safety and efficacy of human and veterinary drugs and devices, and the safety of food and color additives is placed on the sponsor (manufacturer) of the regulated product.
Basic information
Public agencies (FDA, EPA, OECD, etc) are responsible for reviewing the sponsor’s test results and determine if they demonstrate the product’s safety and efficacy.
Only when the agencies are satisfied that safety and efficacy have been established adequately is the marketing of the product permitted.
Nonclinical laboratory studies
GLP is needed for: GLP is not needed for:
•Nonclinical safety studies of development of drugs
•Agricultural pesticide development
•Development of toxic chemicals
•Food control (food additives)
•Test of substance with regard to explosive hazards
•Basic research
•Studies to develop new analytical methods
•Chemical tests used to derive the specifications of a marketed food product
Do other countries follow GLPs?
United States Japan 30 member nations of the OECDUKCanadaAustraliaMany other countries
Governmental Agencies - US
Federal Insecticide,Fungicide and Rodenticide Act
(F IFR A)
Toxic Substance Control Act(T SC A)
Environm ental Protection Agency(EPA)
Federal Food, Drug andCosm etic Act
(FFD C A)
Food and Drug Adm inistration(FDA)
United States
Scope of US agency GLPs
EPA TSCA All studies relating to health effects,
environmental effects and chemical fate testing Data required by testing consent agreements
and test rules
Scope of US agency GLPs
EPA FIFRA Studies that support applications for research or
marketing permits for pesticide products regulated by EPA
Scope of US agency GLPs
FDA FFDCA Nonclinical laboratory studies that support
applications for research or marketing permits for products regulated by FDA
Includes food and color additives, animal food additives, human and animal drugs, medical devices for humans, biological products and electronic products
Governmental Agencies - Japan
M inistry of Agriculture, Forestryand Fisheries
(M A FF)
M inistry of Econom y, Tradeand Industry
(M E T I)
M inistry of Health, Labourand W elfare
(M H LW )
Japan
International GLPs
Generally studies at WIL are conducted under GLPs from US, Japan and/or OECD Many protocols list all
three Formal claims of
compliance with other national regulations should be avoided, if possible
International GLPs
Key areas of difference QA responsibilities Management responsibilities Study director responsibilities Test article characterization Multi-site Studies
Historical Perspectives
Historical Perspectives
Underlying assumption at the FDA Reports submitted by
the sponsors accurately described study conduct and precisely reported the study data.
Historical Perspectives Mid-1970s
FDA suspicion during review of studies submitted by a major pharmaceutical manufacturer (G.D. Searle & Co.) in support of New Drug Applications (NDAs) for two important therapeutic products. Data inconsistent Unacceptable laboratory practices Deliberately tried to minimize chance of toxic
results Impossible to draw conclusions regarding
toxic potential of tested products
Historical Perspectives
FDA requested a “for cause” inspection of the manufacturer’s laboratories to determine the cause and extent for the discrepancies Revealed defects in design, conduct and
reporting of the studies Further inspections at other sites
revealed similar problems.
FDA’s Reaction
Alarm that many of the
studies on which proof of
safety had been based
could be invalid. Task forces formed quickly FDA GLPs proposed Nov. 19, 1976 FDA GLPs finalized 1979
EPA follows suit
EPA issued almost identical regulations in 1983.
EPA GLPs extensively amended in 1989 to encompass all pesticide research data.
Too Abstract and Historical?
What product tested at Searle have most of us
consumed?
Aspartame
Why comply?
Compliance with GLPs promotes the quality and integrity of test data
An inspector must be able to easily determine Why, how and by whom the work was done Who was in control What equipment was used Results obtained Any problems and how they were overcome
Research Misconduct
…fabrication, falsification or plagiarism in proposing, performing or reviewing
research, or in reporting research results…does not include honest error or differences
of opinion.
Federal Policy on Research Misconduct
Office of Science Technology and Policy
Executive Office of the President
December 6, 2000
Basic GLP PrinciplesStudy IntegrityStudy Integrity-Reconstruction-Proper data acceptance/rejection
Research IntegrityResearch Integrity-Training of personnel-Responsibilities-Record security-Checks and controls-Confidentiality
Data IntegrityData Integrity-Accuracy-Completeness-Consistency
Integrity Affects….
Data points
Each non-clinical study
The regulatory submission
The work/career of an investigator
All of the research conducted at a laboratory
Public health, safety and confidence in scientific research
Flexibility vs Requirements
GLPs do not specify exactly how everything is to be done
Flexible
SOPs shall set forth in sufficient detail... Equipment shall be adequately
inspected, cleaned and maintained Animal cages…shall be cleaned and
sanitized at appropriate intervals QAU shall inspect each study at intervals
adequate to assure the integrity of the study
Required
SOP deviations shall be documented… Written records shall be maintained for
all inspection, maintenance, testing… Use of pest control materials shall be
documented Maintain a current summary of training
and experience and job description for each individual...
Protocol
Protocol
Every study needs an approved protocol that contains at least: Descriptive title and purpose of the study ID of test, control and reference substance Name and address of the sponsor and
testing facility Appropriate dates Justification for selection of test system
Protocol
The number, body weight, sex, source of supply, species, strain, substrain and age of the test system
Procedure for ID of the test system Description of the experimental design,
including control of bias A description of the diet, including
acceptable levels of contaminants, if applicable
Route of administration and the reason for its choice
Protocol
Each dosage level in appropriate units and the method and frequency of administration
Type and frequency of tests, analyses and measurements
Records to be maintained Date of protocol approval by the sponsor
and the dated signature of the study director Proposed statistics
Protocol
Changes or revisions of an approved protocol and the reasons therefore shall be documented, signed by the study director, dated and maintained with the protocol
Standard Operating Procedures
SOPs
SOPs
Management-approved Insure the quality and integrity of data Immediately available manuals and
SOPs relative to the procedures being performed
Historical file of SOPs
SOPs
Established for: Test system room preparation Test system care Receipt, ID, storage, handling, mixing and
method of sampling of the test, control and reference substances
Test system observations Laboratory or other tests Handling of test systems found moribund or
dead during study Necropsy or postmortem examination
SOPs
Established for: Collection and ID of specimens Histopathology Data handling, storage and retrieval Maintenance and calibration of
equipment Transfer, proper placement and ID of
test systems
SOPs
Deviations must be authorized by the study director and documented in the raw data
Significant changes to SOP must be authorized in writing by management
Note: Instructions in the protocol override SOP
Conduct of a Study
Conduct of a Study
Must be conducted in accordance with the protocol
Animals must be monitored in conformity with the protocol
Specimens must be identified by test system, study, nature and date of collection
If histopathology is required, the pathologist must have records of gross findings
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You might be wondering…
What does this all mean?
How do we make it work?
Where do I fit in?
ProtocoProtocoll
Final Final ReporReportt
Animal Animal CareCare
SOPsSOPsQAQA
ArchivesArchives
Test Test SysteSystemm
Study Study DirectorDirector
Raw Raw DataData
Organization and Personnel
Organization and Personnel
Study Director
Quality Assurance
Personnel
Management – Designates study director; Assures characterization; Assures availability
Study director – Single point of study control; Responsible for GLP compliance
QA – Monitors each study; Reports to management; Entirely separate and independent
Personnel – Sufficient number to conduct the study; adequately trained; avoid contamination
Personnel
Must be knowledgeable in GLPs as applicable to involvement in the study
Must have documented education, training and experience to perform assigned functions
Sufficient number of personnel to perform the work in a timely and proper manner
Personnel
Personal sanitation and health precautions to avoid contamination
Access to the protocol and applicable SOPs
Responsible for recording raw data promptly and accurately and in compliance with GLPs
Study Director
The single point of study control Has overall responsibility for the conduct,
interpretation, analysis, documentation and reporting of the study.
Must assure the protocol is approved and followed
Must assure all data and unanticipated events are accurately recorded and verified
Study Director
Assure unforeseen circumstances that may affect the quality and integrity of the study are noted when they occur, and corrective action is taken and documented.
Test systems are as specified in the protocol.
Study Director
Must assure that all raw data, documentation, protocols, specimens and final report are transferred to the archives during or at the close of the study.
Sign the GLP compliance statementSign the GLP compliance statement Takes Responsibility for GLP Takes Responsibility for GLP
compliancecompliance
Quality Assurance Unit
Responsible for monitoring each study to assure management that the following comply with GLPs: facilities equipment personnel methods practices records controls
Quality Assurance Unit
Entirely separate from the conduct of the study
Conduct inspections and maintain records of the inspections
Maintain the master schedule Maintain copies of all protocols Keep management informed of the
status of each study
Quality Assurance Unit
Make sure no protocol or SOP deviations occurred without proper authorization and review
Assure the final report accurately describes the study
Provide QA statement in the final report Agency inspection can include QA
records, but not inspection findings
Management
Designate a study director before the study is initiated
Replace the study director promptly if necessary
Assure there is a Quality Assurance Unit Assure that test, control and reference
substances or mixtures have been appropriately tested for identity, strength, purity, stability and uniformity
Management
Assure that personnel, resource, facilities, equipment, materials and methodologies are available as scheduled
Assure that personnel clearly understand the functions they are to perform
Management
Assure that deviations reported by QAU are communicated to the study director and corrective actions are taken and documented
Multi-Site Studies
Multi-Site Studies
Study director is single point of study control
Clear lines of communication between the Study Director, Principal Investigator, QA and study personnel
Multi-Site Studies
If needed, a Principal Investigator is designated appropriately trained, qualified and
experienced Principal Investigator ensures that the
delegated phase(s) of the study are conducted in accordance with applicable GLPs.
Multi-Site Studies Principal Investigator
An individual who, for a multi-site study, acts on behalf of the Study Director and has defined responsibility for delegated phases of the study. The Study Director’s responsibility for the overall conduct of the study cannot be delegated to the Principal Investigator(s); this includes approval of the study plan and its amendments, approval of the final report, and ensuring all GLPs are followed.
Multi-Site Studies
Study plan (protocol) and final report identify and define the role of any Principal Investigator(s) and any test facilities and test sites involved in the conduct of the study.
Multi-Site Studies
SOP deviations acknowledged by the Study Director and the Principal Investigator.
Deviations from the study plan (protocol) should be described, explained, acknowledged and dated in a timely fashion by the study director and/or principal investigator(s) and maintained with the raw data.
Test, Control and Reference Substances
US EPA GLP Definitions
Differences in GLP Definitions for Test, Control and Reference Substances
FDA Test & Control Articles
OECD Test & Reference (Control) Substances Vehicle (Carrier)
MOHW Test & Control Articles
MAFF Test & Control Substances (no definitions)
METI Test & Control Substances
Test Substance A substance or mixture administered or added to a test
system in a study, which substance or mixture: 1) Is the subject of an application for a research or marketing permit supported by the study, or is the contemplated subject of such an application; or 2) Is an ingredient, impurity, degradation product, metabolite or radioactive isotope of a substance described by paragraph (1) of this definition, or some other substance related to a substance described by that paragraph, which is used in the study to assist in characterizing the toxicity, metabolism, or other characteristics of a substance described by that paragraph.
Control Substance
Any chemical substance or mixture, or any other material other than a test substance, feed, or water, that is administered to the test system in the course of a study for the purpose of establishing a basis for comparison with the test substance for known chemical or biological measurements.
Reference Substance
Any chemical substance or mixture, or analytical standard, or material other than a test substance, feed, or water, that is administered to or used in analyzing the test system in the course of a study for the purposes of establishing a basis for comparison with the test substance for known chemical or biological measurements.
Vehicles and Carriers
US EPA GLP Definitions
Vehicle
Any agent which facilitates the mixture, dispersion, or solubilization of a test substance with a carrier.
Carrier
Any material, including but not limited to feed, water, soil, nutrient media, with which the test substance is combined for administration to a test system.
Facilities
Facilities
Must be of suitable size and construction To avoid contamination To facilitate the proper conduct of studies To ensure proper separation of species To provide separate areas, as
appropriate for the diagnosis, treatment and control of diseases
Facilities
Regulation of environmental conditions temperature humidity photoperiod
Facilities
Storage areas separated from test system and protected against infestation or contamination feed bedding supplies equipment
Facilities
Separate areas to preserve the identity, strength, purity and stability of substances and mixtures Receipt and storage of the test, control and
reference substances Mixing of the test, control and reference
substances with a carrier Storage of the test control and reference
substance mixtures
Facilities
Separate laboratory space for routine and specialized procedures required by studies
Space for archives Limited to access by authorized
personnel only For storage and retrieval of all raw data
and specimens from completed studies
Animal Care
Animal Care
SOPs for housing, feeding, handling and care
Newly received animals shall be isolated and health status evaluated
At the initiation of a study, animals shall be free of any disease or condition that might interfere with the study
Animal Care
Identification Separation of species and studies Cages, racks, pens, enclosures, etc.
shall be cleaned and sanitized at appropriate intervals
Feed and water analyzed periodically Bedding shall not interfere with the
study and be changed as necessary
Animal Care
Use of pest control must be documented
Cleaning and pest control materials must not interfere with the study
Animals must be acclimated to environmental conditions
Animal Care
If an animal contracts a disease during a study Isolated, if necessary May be treated if treatment does not
interfere with the study Diagnosis, authorization of treatment,
description of treatment and each date of treatment must be documented
Equipment
Equipment design
Equipment used in the generation, measurement or assessment of data and equipment used for facility environmental control shall be of appropriate design and adequate capacity to function according to the protocol and shall be suitable located for operation, inspection, cleaning and maintenance.
Equipment Maintenance and Calibration
Adequately inspected, cleaned and maintained
Equipment used for the generation, measurement or assessment of data shall be adequately tested, calibrated and/or standardized
Equipment Maintenance and Calibration
SOP must include methods, materials and schedules for: Routine inspection Cleaning Maintenance Testing Calibration and/or Standardization
Equipment Maintenance and Calibration
SOP shall specify, when appropriate, remedial action to be taken in the event of failure or malfunction of equipment.
SOP shall designate the person responsible for the performance of each operation
Equipment Maintenance and Calibration
Written records shall contain be maintained of all: Inspection Maintenance Testing Calibrating and/or Standardizing operations
Equipment Maintenance and Calibration
Records must contain the date of operation and describe whether maintenance was routine and followed SOP.
Records must be kept of nonroutine repairs as a result of failure and malfunction. Nature of defect How and when defect was discovered Any remedial action taken
Good Documentation is the PROOF of What You Do
Golden Rules
1. If it isn’t written down, it didn’t happen.
2. If it isn’t written down correctly or legibly, it didn’t happen either.
3. Must be able to determine who did what and when they did it.
Raw Data
Any laboratory worksheets, records, memoranda, notes or exact copies thereof, that are the result of original observations and activities of a study and are necessary for the reconstruction and evaluation of the report of that study.
GLP definition from 21 CFR 58, 40 CFR 160, 40 CFR 792
“Raw Data” Proof
Raw Data may include photographs, microfilm or microfiche copies, computer printouts, magnetic media, including dictated observations, and recorded data from automated instruments.
GLP definition from 21 CFR 58, 40 CFR 160, 40 CFR 792
“Raw Data” Proof All data generated during the conduct of a study, except
those that are generated by automated data collection systems, shall be recorded directlyrecorded directly, promptlypromptly and legiblylegibly in inkink.
All data entries shall be dated on the date of entrydated on the date of entry and signed or initialed by the person entering the signed or initialed by the person entering the datadata.
Any changechange in entries shall be made so as not to not to obscure the original entryobscure the original entry, shall indicate the indicate the reasonreason for such change, and shall be dated and dated and signed or identified at the time of the changesigned or identified at the time of the change.
GLP definition from 21 CFR 58, 40 CFR 160, 40 CFR 792
“Raw Data” Proof In automated data collection systems, the
individual responsible for direct data individual responsible for direct data inputinput shall be identified at the time of data identified at the time of data inputinput.
Any changechange in automated data entries shall be made so as not to obscure the original not to obscure the original entryentry, shall indicate the reasonindicate the reason for change, shall be dateddated, and the responsible responsible individual shall be identifiedindividual shall be identified.
GLP definition from 21 CFR 58, 40 CFR 160, 40 CFR 792
“Raw Data” Proof
Raw data shall be sufficiently detailed to allow reconstruction of the study, so that such reconstruction is capable of generating SIMILAR RESULTS and CONCLUSIONS.
You still need to document what you did - even if the protocol spells out the requirement. (remember the golden rules?)
“Raw Data” Proof
All experimental data, including
observations of unanticipated
responses, shall be ACCURATELY
recorded and VERIFIED.
Rules for Good Documentation
Make original hand-written entries directly into
notebook/logbook or appropriate study record
Record legibly using indelible ink Use a ball-point pen
Do not use pencil/colored ink
Do not use felt tip (water soluble) pens
Affix loose papers into notebooks
Label data with pertinent information (WIL-#)
Sign/date lab records daily as work progresses
Rules for Good Documentation
Draw a large diagonal line through unused or
blank pages
Never erase/obliterate an entry
To correct errors Line through an incorrect entry
Add the correct entry
Document the reason for the change or correction
Initial/Date
“Do Not” Documentation Practices
Do Not scribble out mistakes (obscures entry) Do Not write correct entries over top of
incorrect entries (writeovers obscure original entries)
Do Not forget to enter all required information Do Not forget to initial and date the entry Do Not use colored ink/pencil/white-out Do Not leave mistakes uncorrected (check
your entries)
Good Documentation Rules
Do take time, commitment and attention to detail by all employees
The time spent doing the work correctly
the first time will prevent, or at least
minimize, time-consuming and costly
reviews, corrections, and time/money
involved in repeating work conducted
incorrectly.
Good Documentation Rules
Ultimately the most dangerous
price for poor documentation is
non-compliance which could
have devastating effects on the
company, your employment and
other people’s lives.
Reporting of Study Results
The Final Report
Final Report
Must be written for each study and GLPs list minimum components
Must be signed and dated by the study director
Corrections or additions must be in the form of an amendment by the study director.
A copy must be maintained by the sponsor and the test facility
Storage and Retrieval of Records and Data
Archives
Archives
All raw data, documentation, records, protocols, specimens and final reports shall be retained in the archives
Orderly, secure storage and expedient retrieval of all items
Conditions of storage shall minimize deterioration
An individual shall be identified as responsible for the archives
Retention of Records
Length of retention is dependent upon regulation
Some items are not stable and may not need to be retained for the entire retention period
Master schedule, copies of protocols, records of QA inspections, training records, equipment records need to be retained for the retention period
Enforcement and Effects of Non-Compliance
Enforcement of GLPs
Each government agency may perform inspections of any laboratory facility within its jurisdiction at reasonable times and in a reasonable manner.
Inspections may be Routine – periodic determination of the
lab’s compliance; may include data audit. For cause – conducted less frequently;
may be triggered by suspicion or previous non-compliance.
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Regulatory Inspections:What will they do & what can they see?
An Investigator may physically observe any area, equipment or process Facility tour Observe in-progress study activities Interview individuals Perform process inspections (e.g., following
samples from collection through analysis) Look at peripheral equipment such as HVAC
systems, etc.
Regulatory Inspections
FDA inspections are typically unannounced.
EPA typically gives notice prior to inspection.
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Regulatory Inspections:Do Not give these to the Investigator…
Quality Assurance Audits Personnel information Financial Information Gifts/Company Promotional
Materials
Agency Inspections
If a testing facility were to refuse an inspection or be found to have conducted studies that were not in compliance with GLPs, the agency would refuse to approve test articles that were tested at that facility.
In addition, management personnel may be subject to civil or criminal penalties.
What does non-compliance mean?
The study did not follow some part of GLPs
Data are false or misleading Data contain significant omissions Inspection was refused
Statement of compliance or non-compliance
EPA and OECD require the extent to which GLPs were followed to be described in the final report
Three options Study complied with GLPs Study (or parts thereof) did not comply
with GLPs Don’t know if study complied with GLPs
Everyone Wins When You Follow Good Laboratory Practices
Late Documentation
FDA Warning Letter In the absence of contemporaneous
documentation, FDA does not have confidence that the final report can accurately and completely describe these operations more than 18 months after the study was conducted.
Late Documentation
FDA Warning Letter The Study Director has not noted
unforeseen circumstances or deviations that may affect the quality and integrity of nonclinical studies when they occurred and failed to document what corrective actions, if any, were taken at that time. In several cases, deviations that occurred were noted six months to more than one year later.
Examples
Date corrections 6/15/2003 (incorrect date) 6/15/2003 (line through entire entry)
not 6/15/2003 6/16/2003 (write the correct entry) footnote the reason for change initial and date