GLP DRA.pptx

GLP = good laboratory practice guidelines for NON clinical study

1. Good Laboratory Practice (GLP) Regulations Name = Diwakar shukla M .pharm DRA Chitkara university

2. 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, reported and archived. GLP is sometimes confused with the standards of laboratory safety like wearing safety goggles.

3. WHY WAS GLP CREATED? In the early 70’s FDA became aware of cases of poor laboratory practice all over the United States. FDA decided to do an in-depth investigation on 40 toxicology labs. They discovered a lot fraudulent activities and a lot of poor lab practices. Examples of some of these 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 test systems

4. History of GLPs (Why?) Two Famous Examples of FDA Inspections of Toxicology Studies G.D. Searle and Company Questionable test data Sloppy work Untrained personnel Poor data collection Poor analysis Poor review and reporting practices Industrial Bio-Test Laboratories (IBT) Scientific misconduct Fabrication of Data Replacement of dead animals with healthy ones Changes in the Interpretation of Histopathology Slides Changes in Report Conclusions to make them look more favorable Still goes on today!!!

5. Introduction The FDA requires manufactures of human drugs, biopharmaceuticals and biological products, animal drugs, medical devices, electronic and food additives to demonstrate the safety of their products prior to use in humans or in the case of animals , prior to use in the indicated species Compliance with 21 CFR Part 58 – the Good Laboratory Practice (GLP) regulation is intended to assure the quality and integrity of the safety data used to support the applications for research or marketing permits for FDA regulated products. GLP Compliance allows for accurate reconstruction of the conduct of a nonclinical study b ased on quality record keeping and reporting .

6. GLP Regulations Vary with Agencies and Nations FDA - FD&C Act 1938 and 21CFR58 FDA is currently revising and updating US EPA – Applies to chemical substances, mixtures, pesticides OECD (North America, Europe and Asia) – ‘EU Requirements’ Similar to FDA GLPs but includes EPA compounds MHLW (Japanese FDA) Similar to FDA GLPs Mutual Recognition Agreement US FDA, EU and Japanese FDA generally accept each others GLPs (report should state that it meets all 3 agency GLPs) However they do not accept C hinese GLPs FDA, EPA and MHLW GLPs are regulations and required by law, OECD GLPs are voluntary Requirements for all 3 should be met in the Toxicology and Safety Pharmacology reports In 1981 an organization named OECD (organization for economic co-operation and development ) produced GLP principles that are international standard.

7. The Organizations for Economic Co-operation and Development (OECD) principles of GLP were first developed in 1978 by an international group of experts under the special programme on the control of chemicals. The GLP for the non clinical laboratory studies published by the US Food and Drug Administration (FDA) in 1976 provided the basis for the work of the expert group. It utilized common managerial and scientific practices and experience from various national and international sources. These principles of GLP were adopted by the OECD council in 1981. Later in 1995 and 1996 team of new group of experts revised and modified the principles of GLP and the current one is based on the consensus reached by that group. In India, a national GLP compliance monitoring authority was established by the Department of Science and Technology (DST) in 2002. Presently India enjoys the status of provisional member of the OECD for GLP. India is an observer to the OECD’s working group on GLP and also a member of the OECD test guidelines programme . The national GLP programme functions through an Apex body which consist of the following members . Good Laboratory Practices has been made as law by introducing it as Schedule L-1 which is a New Schedule under Drugs and Cosmetics Rules, 1945 vide Gazette notification no GSR 780 (E) 10-11-2008 with effect from 1-11-2010. Consequent to this amendment, Rule 74, 78 and Rule 150E of the Drugs and Cosmetics Rules, 1945 have been amended. It involves a number of good practices in the Quality Control laboratory which are to be undertaken to carry out an analysis with a defined degree of Accuracy & Precision.

8. GLP and GMP GMP: Protect the integrity and quality of manufactured product intended for human use . GLP: Protect the integrity and quality of laboratory data used to support a product application.

9. GLPs prevent Fraud GLPs were designed to ensure data quality and to reduce fraud by requiring specific documentation be kept regarding several key areas including: L aboratory staff F acilities and Operations Equipment T est and Control Articles Protocol Conduct of study (what happened) Q uality Assurance Archiving of data, records and specimens Specific Retention Time required for all for the above for marketed drugs (different for discontinued drugs).

10. Definition of a Study (1/4) A ‘nonclinical laboratory study’ means in vivo or in vitro experiments in which test articles are studied prospectively in test systems under laboratory conditions to determine their safety (not in the clinical trials or field trials in animals) . 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. Types of GLP Studies (2/4) Contract Research Organization or In-house Studies: Acute, Subchronic, Chronic Studies Carcinogenicity and Genotoxicity Studies Development and Reproductive Toxicology Studies Dermal/Eye/Venous/Muscle Irritation Studies Immunogenicity/Antigenicity Studies Bioanalytical Studies of Samples from Dose Groups of Study Animals (Pharmacokinetics/Toxicokinetics) Validation of analytical methods for GLP studies (TK and formulation analysis) Safety Pharmacology Studies (Cardiovascular, Respiratory and CNS)

12. External Types o f Studies (3/4) Laboratories that analyze samples that are generated by GLP studies, they do not conduct the study (can be separate from the laboratory that conducts the study): Clinical Chemistry Hematology Urinalysis Histology and Pathology Toxicokinetics Validation of analytical methods for GLP studies (TK and formulation analysis) Immunogenicity Assays

13. Types of Studies N ot Covered by GLP (4/4) Basic Research (Primary and Secondary Pharmacology) Proof of Concept Studies Exploratory Pharmacokinetic Studies (DMPK) Dose-Range Finding Studies (Toxicology) Primary Pharmacodynamic Studies Analytical Quality Control Testing for Clinical and Commercial Studies Stability Testing of Clinical and Commercial Products Studies using Human Subjects Field Trials in Animals

14. FDA GLP Subparts and Sections of 21CFR58 (1/10) (Subpart A – General Provisions) Subpart A 58.3: Definitions Subpart A 58.1– Scope 58.3 Definitions 58.10 Applicability to Studies performed under Grants and Contracts 58.10 Inspection of a testing facility Act Test Article Control Article Nonclinical Laboratory Study Applications for Research or Marketing Permit IND / NDA / BLA Notice of Claimed Investigational Exemptions for a New Animal Drug / New Animal Drug Application Application for Premarket Approval of a Medical Device / Product Development Protocol for a Medical Device Sponsor Testing Facilities Person Test System Specimen Raw Data Quality Assurance Unit Study Director Batch Study Initiation Date Study Completion Date

15. FDA GLP Subparts and Sections of 21CFR58 (2/10) (Subpart A – General Provisions) Subpart A: 58.10 Application to Studies Performed under Grants and Contracts Applies to CROs to perform all or part of a nonclinical laboratory study submitted to the FDA as part of an application Sponsor is responsible to tell the CRO the studies are GLP Protocol includes a statement about the regulatory standards under which the study will be conducted (FDA, OECD, EPA, MHLW) Implied that the site should be inspected (audited) by the sponsor if never inspected by the FDA

16. FDA GLP Subparts and Sections of 21CFR58 (3/10) (Subpart B – Organization and Personal) 58.29 - Personnel (Job Descriptions / Training Records) “ 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.” 58.31 - Testing Facility Management Responsible for approving a test facilities, Standard Operating Procedures (SOPs) Assigning a Study Director prior to initiation of study and replacing as necessary Responsible for Test and Control Articles Make sure the study complies with GLP 58.33 - Study Director Overall responsibility for the study’s design, conduct, reporting and compliance with GLPs and SOPs Document and assess all circumstances and if their impact on the study and corrective actions Not the principle investigator/ contributing scientist if the study is conducted over different sites 58.35 - Quality Assurance Unit Responsible for ensuring that studies are conducted in accordance with GLPs Maintain a master schedule of GLP studies and inspect the CRO according to the schedule as defined by SOPs to insure GLP compliance Responsibility – Audit everything

17. FDA GLP Subparts and Sections of 21CFR58 (4/10) (Subpart C - Facilities) “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.” 58.41 – General 58.43 – Animal Care F acilities 58.45 – Animal Supply Facilities 58.47 – Facilities for handling test and control articles 58.49 – Laboratory Operation Areas 58.51 - Specimen and Data S torage F acilities

18. FDA GLP Subparts and Sections of 21CFR58 (5/10) (Subpart D - Equipment) 58.81 – Equipment Design Computer systems are not covered under GLPs but are included in an FDA inspection and must insure the quality and integrity of the study 21CFR11 – Electronic Records and Electronic Signatures established the criteria the FDA uses for electronic records, electronic signatures and hand written signatures executed to electronic records to be trustworthy 58.63 Maintenance and Calibration of Equipment SOPs establish the maintenance and the frequency of calibration of all equipment

19. FDA GLP Subparts and Sections of 21CFR58 (6/10) (Subpart E – Test Facility Operation) 58.81 – Standard Operating Procedures (SOPs) Intended to ensure that laboratory procedures ad processes are consistently performed by all individuals in the facility Must be available to all staff anywhere in the facility Mandatory review of all SOPs as needed by Facility Management The protocol describes ‘what’ needs to be done, SOPs describe ‘how’ All deviations from SOPs need to be documented in the records and report by the study director and the impact on the study assessed If specific instructions in the protocol are different than the SOP, then this is a deviation of the SOP and needs to be documented 58.83 – Reagents and Solutions 58.90 - Animal Care Animals of different species shall be housed in separate rooms when necessary. Animals of the same species, but used in different studies, should not ordinarily be housed in the same room when inadvertent exposure to control or test articles or animal mix-up could affect the outcome of either study. If such mixed housing is necessary, adequate differentiation by space and identification shall be made .

20. FDA GLP Subparts and Sections of 21CFR58 (7/10) (Subpart F – Test and Control Articles) 58.105 – Test and Control Article Characterization Test article - is any food additive, color additive, drug, biopharmaceutical, biologic product, medical device or electronic product intended for human use Control article – any article other than the test article intended to be used as a control in the study GLPs require the characterization, stability testing sample retention and inventory of test and control articles 58. 107 – Test and Control Article Handling Requires the CRO to document the proper storage, handling, distribution, identification, receipt and distribution of the article, showing the ‘chain of custody’ 58.113 – Mixtures of Articles with Carriers Analytical methods to demonstrate the article is consistently mixed with the carrier (usually sampling from the top, middle and bottom of the mixture is sufficient.

21. FDA GLP Subparts and Sections of 21CFR58 (8/10) (Subpart G – Protocol for and Conduct of a Nonclinical Study) 58.120 – Protocol A formal plan of the study ; 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 Nonclinical L aboratory Study The execution, changes to and deviations during the study need to be documented and the impact assessed and recorded. All records in ink and any changes require initials and date of the change. General a single line through the data.

22. 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. The protocol shall contain, as applicable, the following information: ( 1) A descriptive title and statement of the purpose of the study. ( 2) Identification of the test and control articles by name, chemical abstract number, or code number. ( 3) The name of the sponsor and the name and address of the testing facility at which the study is being conducted. (4) The number, body weight range, sex, source of supply, species, strain, substrain , and age of the test system. (5) The procedure for identification of the test system. (6) A description of the experimental design, including the methods for the control of bias. (7) A description and/or identification of the diet used in the study as well as solvents, emulsifiers, and/or other materials used (8) Each dosage level, expressed in milligrams per kilogram of body weight or other appropriate units, of the test or control article to be administered and the method and frequency of administration. (9) The type and frequency of tests, analyses, and measurements to be made. (10) The records to be maintained. (11) The date of approval of the protocol by the sponsor and the dated signature of the study director. (12) A statement of the proposed statistical methods to be used.

23. FDA GLP Subparts and Sections of 21CFR58 (9/10) (Subpart J – Records and Reports) 58.185 – Reporting of Nonclinical Laboratory Results A final report shall be prepared for each nonclinical laboratory study 58.190 – Storage and Retrieval of Records and Data Establishment of an Archive and Archivist for the storage of all raw data, documentation, protocols, specimens, and interim / final reports and kept in a secure storage area in accordance with 58.195 58.195 – Retention of Records

24. FDA GLP Subparts and Sections of 21CFR58 (10/10) (Subpart K – Disqualification of Testing Facilities) 58.200 - Purpose 58.202 – Ground for disqualification 58.204 – Notice of and opportunity for hearing on proposed disqualification 58.206 – Final Order of Disqualification 58.210 – Actions upon Disqualification 58.213 – Public disclosure of information regarding disqualification 58.215 – Alternatives or additional action to disqualification 58.217 – Suspension or termination of a testong facility by a sponsor 58.219 – Reinstatement of a disqualified testing facility

25. FDA Inspection of GLP Laboratories and the Consequence of Noncompliance All laboratories in the USA can be inspected by the FDA. The FDA needs to request foreign laboratories to conduct GLP inspections. Bioresearch Monitoring Program (BIMO) to address both domestic and international inspections of nonclinical laboratories operating under US GLPs (Compliance Program Guidance 7348.808) 483s (Inspection Observations) Warning Letters Consent Agreements Disqualifications

26. Quality Audit : An audit or an inspection is a methodical evaluation that should be performed in cooperation with the people whose operations are being audited The objective of auditing a laboratory’s quality program is to evaluate the activities and existing documentation and to determine if they meet predetermined standards. A total quality program in a laboratory is usually developed to assure that all activities are performed with the objective of meeting certain standards, both internal and external In addition to the QA review of planning activities, QA performs three types of audits/ inspections: Study-based inspections/audits; Facility/Systems-based inspections/audits; Process-based inspections/audits. Audit & goals

27. Competency is the key objective of any laboratory quality program. Laboratory accreditation is a “formal recognition that a testing laboratory is competent to carry out specific tests or specific types of tests ”. The accreditation of a laboratory can be either an internal or external standard, or both. The audit for accreditation is an on-site examination of the laboratory to determine if it meets the accreditation criteria. Audit & goals

28. Audit tools 1. Cause and effect diagram (also known as Ishikawa Diagram/ fishbone diagram)e.g. toxicity study

29. Audit tools 2 .  Check sheet

30. Audit tools 3.   Pareto Diagram

31. Audit tools 4 .   Histogram

32. Audit tools 5.  Run chart,

33. Audit tools 6 .   Scatter Diagram,