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Good Laboratory Practices & Good Clinical Practices :

Good Laboratory Practices & Good Clinical Practices Presented by:- Mr. Swapnil L. Patil M.Pharm (Semester-2) Department of Pharmaceutics Pad. Dr. D. Y. Patil College of Pharmacy, Akurdi, Pune, Maharashtra, India, 411018 . 1

Good Laboratory Practices :

Good Laboratory Practices . 2


Contents: Introduction History Objective Rules and regulation Noncompliance 3


4 GLP : GOOD LABORATORY PRACTICE GLP is an FDA regulation . Definition : GLP embodies a set of principles that provides a framework within which laboratory studies are planned , performed , monitored, recorded, reported and archived . GLP is sometimes confused with the standards of laboratory safety like wearing safety goggles.


GOOD LABORATORY PRACTICE GLP applies to nonclinical studies conducted for the assessment of the safety or efficacy of chemicals (including pharmaceuticals). GLP helps assure regulatory authorities that the data submitted are a true . 5


HISTORY The formal regulatory concept of “Good Laboratory Practice” (GLP) originated in the USA in the 1970’s. The FDA’s publication of Proposed Regulations on GLP in 1976, with establishment of the Final Rule in June 1979 (21 CFR 58). In 1981 an organization named OECD produced GLP principles that are international standard. 6


7 WHY WAS GLP CREATED? In the early 70’s FDA became aware of cases of ( PLP ) poor laboratory practice all over the United States. FDA decided to do an in-depth investigation in 40 toxicology labs. They discovered a lot fraudulent activities and a lot of poor lab practices. Examples of some of these ( PLP ) poor lab practices found were Equipment not been calibrated to standard form , therefore giving wrong measurements. Incorrect/inaccurate accounts of the actual lab study Inadequate plan


FAMOUS EXAMPLE One of the labs that went under such an investigation made headline news. The name of the Lab was Industrial Bio Test. This was a big lab that ran tests for big companies such as Procter and Gamble. It was discovered that mice that they had used to test lotion and deodorants had developed cancer and died 8

Slide 9:

9 Industrial Bio Test lab threw the dead mice and covered results deeming the products good for human use. Those involved in production, distribution and sales for the IBT lab eventually served jail time.


10 OBJECTIVES OF 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. Promotes international acceptance of tests.


11 MISSION OF GLP Test systems Archiving of records . Apparatus, material and reagent facilities. Quality assurance programs. Performance of the study. Reporting of study results. Standard operating procedures (SOP)

Slide 12:

21 CFR Part 58: Non-Clinical Laboratory Studies Subpart A: General Provisions Subpart B: Organization and Personnel Subpart C: Facilities Subpart D: Equipment Subpart E: Testing Facilities Operation Subpart F: Test and Control Articles Subpart G: Protocol for and Conduct of a Non-Clinical Laboratory Study Subpart J: Records and Reports Subpart K: Disqualification of Testing Facilities 12

GLP Regulations: Rules and Tools:

GLP Regulations: Rules and Tools Chemical and sample inventory, expiration dates TEST, CONTROL, AND REFERENCE SUBSTANCES Timely reporting, storage of raw data and reports RECORDS AND REPORTS Standard operating procedures FACILITY OPERATION Calibration, logbooks of use, repair, and maintenance EQUIPMENT Maintain adequate space/separation of chemicals from office areas FACILITIES Training records, CVs, GLP training ORGANIZATION AND PERSONNEL Documentation (Tools)‏ GLP Regulations (Rules)‏ 13

Organization and Personnel :

Organization and Personnel 58.29 Personnel (a)“Each individual engaged in the conduct of or responsible for the supervision of a nonclinical laboratory study shall have education , training , and experience , or combination thereof, to enable that individual to perform the assigned functions.” (b)“Each testing facility shall maintain a current summary of training and experience and job description for each individual engaged in or supervising the conduct of a nonclinical laboratory study.” 14

Organization and Personnel :

Organization and Personnel 58.33 Study Director “For each nonclinical laboratory study, a scientist or other professional of appropriate education, training, and experience, or combination thereof, shall be identified as the study director . The study director has overall responsibility for the technical conduct of the study , as well as for the interpretation, analysis, documentation, and reporting of results, and represents the single point of study control .” 58.35 Quality Assurance Unit “A testing facility shall have a quality assurance unit which shall be responsible for monitoring each study to assure management that the facilities, equipment, personnel, methods, practices, records, and controls are in conformance with the regulations in this part. For any given study, the quality assurance unit shall be entirely separate from and independent of the personnel engaged in the direction and conduct of that study.” 15

Slide 16:

Facilities 58.41 General “Each testing facility shall be of suitable size and construction to facilitate the proper conduct of nonclinical laboratory studies. It shall be designed so that there is a degree of separation that will prevent any function or activity from having an adverse effect on the study.” Animal care facilities Animal supply facilities Facilities for handling test and control articles Laboratory operation areas Specimen and data storage facilities 16

Slide 17:

Equipment 58.61 Equipment Design “Equipment used in ... shall be of appropriate design and adequate capacity ...” 58.63 Maintenance and Calibration (a) “The written standard operating procedures ...” (b) “Written records shall be maintained ...” Log book Fit for use Not for GLP use. 17


Equipment Verification (Testing): external check of equipment accuracy (e.g. check balance accuracy against weights at laboratory- no adjustment )‏ Calibration: equipment is adjusted based on comparison to certified or known reference materials (e.g. balance adjusted after comparison to certified weights by trained professional)‏ Standardization: comparison with similar equipment (e.g. use two thermometers of similar design to compare readings)‏ Verification ?? Calibration ? Standardization ? ?? 18

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Protocol , Reports and Records 58.120 Protocol “Each study shall have an approved written protocol that clearly indicates the objectives and all methods for the conduct of the study.” 58.130 Conduct of a Non-clinical Laboratory Study “The nonclinical laboratory study shall be conducted in accordance with the protocol” 58.185 Reporting of Non-clinical Laboratory Study Results “A final report shall be prepared for each nonclinical laboratory study ...” 58.190 Storage and Retrieval of Records and Data “All raw data, documentation, protocols, final reports, and specimens ... shall be retained.” 19

Raw Data:

Raw Data Definitions . “ ’Raw data’ means 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 .” If anyone scribble some notes on a scrap of paper, are those notes considered raw data? 20

Raw Data:

Raw Data examples of raw data :- Logbooks (to record temperatures or equipment use, repair, and maintenance)‏ Field or laboratory notebooks Forms (for field or laboratory observations, chain-of-custody, sample or chemical receipt)‏ Training reports Computer printouts Recorded data from automated instruments Question: What happens if you make a mistake? 21

Standard Operating Procedures (SOP) :

22 Standard Operating Procedures (SOP) 40 CFR Part 160 (EPA GLP regulations)‏ “ Section 160.81 Standard operating procedures. (a) A testing facility shall have standard operating procedures in writing setting forth study methods that management is satisfied are adequate to insure the quality and integrity of the data generated in the course of a study.” Written procedures for a laboratories program. They define how to carry out protocol-specified activities. Most often written in a chronological listing of action steps. They are written to explain how the procedures are suppose to work Standard Operating Procedures (SOP)

Standard Operating Procedures (SOP) :

23 Standard Operating Procedures (SOP) SOPs should accurately reflect how routine tasks are performed Routine inspection, cleaning, maintenance, testing and calibration. Actions to be taken in response to equipment failure. Reviewed on regular basis.

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

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

Possible Violations:

25 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:

26 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 Thus, if it can be shown that such disqualifications did not affect the integrity and outcome of the study itself, or did not occur at all, then the study may be reinstated at the will of the commissioner

Upon Disqualification…:

27 Upon Disqualification… If the commissioner finds that the facility showed a noncompliance, any of the grounds after the hearing, then a final order of noncompliance will be sent to the facility with explanations If a testing facility has been disqualified, any studies done before of after the disqualification will need to be determined as essential to a decision (acceptable or not) If the study is determined unacceptable, then the facility itself may need to show that the study was not affected by the noncompliance that led to the disqualification Once finally disqualified, the facility may not receive or be considered for a research or marketing permit and the study is rejected.

Upon Disqualification…:

28 Upon Disqualification… The commissioner may notify the public and all interested persons, including other federal agencies the facility may have contacted The FDA may ask the other agencies to consider whether to support the facility or not under the disqualification 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

Upon Disqualification…:

29 Upon Disqualification… The FDA may turn it over to the federal, state or local law enforcement The facility’s sponsor may terminate or suspend the facility from doing any non- clinical study for a permit 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:

30 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

Slide 31:

31 Good Clinical Practice

Contents :

Contents Glossary Principles of GCP IEC/IRB Responsibilities Investigator Responsibilities Sponsor Responsibilities Protocols and Amendments Investigator’s Brochure Essential Documents 32


Glossary Adverse drug reaction (ADR) Serious Adverse Event (SAE) Audit Blinding/masking Investigator Protocol Sponsor 33

History of Good Clinical Practice:

History of Good Clinical Practice Prior to an actual set of guidelines to follow for good clinical practice, clinical studies were dangerous and could result in serous disease, or possibly death. The Nuremburg Code of 1947 Experiments performed in Germany during WWII opened the eyes of the world for guidance for clinical testing on humans. The code did set ethical guidelines, but it lacked legislation to back it up. Declaration of Helsinki In 1964, the World Medical Association established recommendations guiding medical doctors in biomedical research involving human subjects. These guidelines influenced national legislation, but there was no set standard between nations. 34


35 GOOD CLINICAL PRACTICE FDA ICH 21 CFR International Electronic Docs. Inf. Consent Financial Disclosure IRBs IND regs. glossary principles IRBs Investigator Sponsor Essential Docs

ICH Guidelines:

ICH Guidelines ICH Guidelines are divided into 4 main topics: Quality Topics – relate to chemical and pharmaceutical quality assurance e.g. Q1 Stability Testing Safety Topics – relate to preclinical studies e.g. S1 Carcinogenicity Testing Multidisciplinary Topics – cross-cutting topics which don’t fit into one of the other categories e.g. M1 Medical Terminology Efficacy Topics – relate to clinical studies in human subjects e.g. E6 Good Clinical Practice; e.g. E2A Clinical Safety Data Management: e.g. E9 Statistical Principles for Clinical Trials 36

FDA Regulations:

FDA Regulations 21 C.F.R. Part 312, Subpart D (Duties of Sponsors, Investigators) – 21 C.F.R. Part 50 (Informed Consent) – 21 C.F.R. Part 56 (Institutional Review Boards) – 21 C.F.R. Part 54 (Investigator Financial Disclosure) 37

What is GCP ?:

What is GCP ? Good Clinical Practice (GCP) is defined as a ‘standard for the design, conduct, performance, monitoring, auditing, recording, analyses and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity and confidentiality of trial subjects are protected’ 38


GCP Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve the participation of human patients. Compliance with this standard provides public assurance that the rights, safety and well-being of trial patients are protected and clinical trial data are credible. 39


GCP Are mainly focused on the protection of human rights in clinical trial. Provide assurance of the safety of the newly developed compounds. Provide standards on how clinical trials should be conducted. Define the roles and responsibilities of - Clinical Sponsors, Clinical Research Investigators, Clinical Research Associates, And Monitors. 40

Principles of ICH GCP:

Principles of ICH GCP Clinical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with GCP and the applicable regulatory requirements. Before a trial is initiated, foreseeable risks and inconveniences should be weighed against the anticipated benefit for the individual trial subject & society . A trial should be initiated and continued only if the anticipated benefits justify the risks. Benefits RISKS 41

Principles of ICH GCP Continued:

Principles of ICH GCP Continued The rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interests of science & society. The available non-clinical & clinical information on an investigational product should be adequate to support the proposed clinical trial. Clinical trials should be scientifically sound, and describe in a clear, detailed protocol. A trial should be conducted in compliance with the protocol that has received prior IRB (or IEC) approval. 42

Principles of ICH GCP Continued:

Principles of ICH GCP Continued The medical care given to, and medical decisions made on behalf of, subjects should always be the responsibility of a qualified physician or, when appropriate, of a qualified dentist. Each individual involved in conducting a trial should be qualified by education, training and experience to perform his or her respective tasks. Freely given informed consent should be obtained from every subject prior to clinical trial participation. 43

Principles of ICH GCP Continued:

Principles of ICH GCP Continued All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation, and verification. The confidentiality of records that could identify subjects should be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory compliance. 44

Principles of ICH GCP Continued:

Principles of ICH GCP Continued 12. Investigational products should be manufactured, handled, and stored in accordance with applicable good manufacturing practice (GMP). They should be used in accordance with the approved protocol 13. Systems with procedures that assure the quality of every aspects of the trial should be implemented. 45

Institutional Review Board (IRB), Independent Ethics Committee (IEC):

Institutional Review Board (IRB), Independent Ethics Committee (IEC) A formally designated group that oversees research involving human subjects. Approves and disapproves human subject research. According to the standards of the community or the institution, the IRB/IEC may require modifications to a protocol to ensure patient safety. 46

IRB Function :

IRB Function • The primary function of an IRB/IEC is to safe guard the rights ,safety ,and well being of all trial subjects . This is accomplished by initial, continuing and annual review. •An IRB should consist of members who collectively have the qualifications and experience to review and evaluate the science , medical aspects, and ethics of the proposed trial. 47

IRB Members :

IRB Members 1.A minimum of five (5) members. 2.One member whose concern is not scientific. 3.One member who has no personal or familial relationship to the institution or trial site. 4.Any member with a conflict of interest may not participate in any part of the review or vote (except to provide requested information). 5.Individuals with special expertise may be invited to assist with areas of unique or complex nature. These will not be voting members. 6.A list of IRB/IEC members and their qualifications should be maintained. 48

IRB/Ethics Committee:

IRB/Ethics Committee All studies must be approved prior to recruiting participants IRB must review all documents given to participants Reporting AEs and Deviations from protocol to the IRB Maintenance of Records 49

Investigator Responsibilities:

Investigator Responsibilities Adequate Resources Recruitment Time Qualified Staff Facilities Training 50

Investigator Responsibilities:

Investigator Responsibilities Medical Care A qualified MD (or dentist) responsible for trial-related medical decisions Provide adequate medical care for AEs or other significant medical condition Inform PCP about participation in trial Make a reasonable effort to ascertain why participant withdrawals from study 51

Investigator Responsibilities:

Investigator Responsibilities Compliance with Protocol Investigator should sign off on protocol Investigator should not implement deviations from protocol If deviations occur, they should be documented and reported at once to the sponsor, the IRB and other regulatory authorities 52

Investigator Responsibilities:

Investigator Responsibilities Progress Reports Written summary of trial status to the IRB Written reports to the sponsor or regulatory authority of any changes affecting the trial Safety Monitoring SAEs should be reported immediately AEs should be reported according to sponsor guidelines Supply sponsor & IRB with requested materials on participant deaths 53

Investigator Responsibilities:

Investigator Responsibilities Premature Termination or Suspension Promptly inform trial subjects Assure appropriate therapy & follow-up Inform sponsor, regulatory authorities & IRB Final Reporting Inform IRB of study completion & a summary of the trial’s outcome Provide sponsor & regulatory authorities with all required reports 54

Investigator’s Brochure:

Investigator’s Brochure Defined as a compilation of the clinical and nonclinical data on the investigational product(s) that are relevant to the study of the product(s) in human subjects. 55

Clinical Trial Protocol:

Clinical Trial Protocol General Information Background Information Trial Objectives & Purpose Trial Design Selection & Withdrawal of Participants Treatment of Subjects Assessment of Efficacy Assessment of Safety 56

Sponsor Responsibilities:

Sponsor Responsibilities Quality Assurance & Quality Control Provide written SOPs Secures agreement between all parties Data handling Contract Research Organization (CRO) Hired by the sponsor to implement trial-related duties Medical Expertise Designated medical personnel to advise on trial-related medical questions and problems 57

Sponsor Responsibilities:

Sponsor Responsibilities Trial Design Designs CRFs Planning analyses Trial Management, Data Handling, Recordkeeping, & Independent Data Monitoring Committee (DMC) Qualified personnel to supervise overall conduct of the study DMC assesses the progress of the clinical trial Maintain SOPs for electronic data processing Inform Investigator of guidelines for record retention 58

Essential Documents for the Conduct of a Clinical Trial:

Essential Documents for the Conduct of a Clinical Trial Preclinical trial commencement During clinical conduct of trial After completion or termination of trial 59

Storage of Essential Documents :

Storage of Essential Documents Sponsor Rule : refer to study protocol FDA Rule : 2 options 2 years following marketing of the drug or, 2 years after IND application is withdrawn if drug was not marketed 60


References 61


References http :// Handbook: good laboratory practice (GLP): quality practices for regulated non-clinical research and development -2nd ed., WHO Library Cataloguing-in-Publication Data, 2nd ed., 7,15-20. 62


References OECD Principles of Good Laboratory Practice (as revised in 1997)" . OECD Environmental Health and Safety Publications ( OECD ) 1 . 1998.,2340,en_2649_34381_2346175_1_1_1_37465,00.html . Schneider, K (1983(Spring)). "Faking it: The case against Industrial Bio-Test Laboratories" . Amicus Journal (Natural Resources Defence Council): 14-26. . . 63

References :

References Tweedale, AC (2011). "Uses of ‘Good Laboratory Practices’ by regulated industry and agencies, and the safety of bisphenol A". J Epidemiol Community Health (BMJ Group) Online First: 15 February 2011 . doi : 10.1136/jech.2010.127761 . Webster, Gregory K. et al. (2005). "JALA Tutorial: Considerations When Implementing Automated Methods into GcP". Journal of the Association for Laboratory Automation ( Elsevier ) 10 (3): 182–191. doi : 10.1016/j.jala.2005.03.003 64


. Question???? 65

Thank you……….:

Thank you………. 66

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