GOOD LABORATORY PRACTICES

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GOOD LABORATORY PRACTICES

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GOOD LABORATORY PRACTICES:

GOOD LABORATORY PRACTICES Presented By: Sumit Kumar Mittal (M.pharma II sem) Department of Quality Assurance I.S.F College of Pharmacy, Moga(Punjab)

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Totality of features and characteristics of a product or service which bear on its ability to satisfy stated or implied needs. Features such as: Design Appearance Reliability Maintainability Service All this leads to fitness for use.

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QA is wider concept that ensures pharmaceutical products are of quality required for intended use. QA= GCP + GLP + GMP + GPP GxPs go hand in hand to achieve the desired quality.

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Good Laboratory Practice (GLP) deals with the organization, process and conditions under which laboratory studies are planned, performed, monitored, recorded and reported. Purposes of GLP regulations are: Assure quality Validity and integrity of test data submitted to FDA

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In the mid-1970s, a “FOR-CAUSE” inspection brought validity of studies under suspect. Issues such as: Personnel Incompetence Improper record keeping Improper design of protocols Improper documentation Non-compliance with audits To overcome these major problems, in December 1978, FDA published final GLP regulations and made compliance with them the law in the United States in June 1979. These regulations were collected in Title 21: "Food and Drugs" of the Code of Federal Regulations (CFR) as Part 58: "Good Laboratory Practice for Nonclinical Laboratory Studies,“ and applied to all nonclinical safety studies.

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Further changes to the GLP rules were proposed in 1984, 1987, and again in 1991 was expanded to incorporate the following: Requirement for a QA department Requirement for protocol preparation (study plan) Characterization of test and control materials Requirement to retain specimens and samples. The principles have expanded to include other scientific activities and devices (such as computers). In Europe, adherence to the principles of GLP is governed by European Union (EU) law and, in compliance with EU Directives, an inspection program confirms that " toxicological studies for the regulatory assessment of industrial chemicals, medicines, veterinary medicines, food and animal feed additives, cosmetics, and pesticides must be conducted in accordance with GLP.“ GLP regulations have also transferred under the umbrella of the OECD as principles of Good Laboratory practices to other countries of Asia .

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GLP starts with preclinical development, for example toxicology studies. Clinical trials are regulated by good clinical practice regulations and manufacturing through GMPs.

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Part 11 is FDA’s regulation on electronic records and signatures and applies for electronic records or to computer systems in all FDA regulated areas. For example, it applies for computers that are used in GLP studies. Independent from Location and Duration of Study: The duration and location of the study is of no importance. For example, GLP applies to short term experiments as well as to long term studies. If a pharmaceutical company subcontracts part of a study to a university, that university still must comply with the same requirements as the sponsor company.

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Code of Federal Regulations Title 21, Volume 1, Revised as of April 1, 2009 TITLE 21--FOOD AND DRUGS CHAPTER I--FOOD AND DRUG ADMINISTRATION DEPARTMENT OF HEALTH & HUMAN SERVICES PART 58: GOOD LABORATORY PRACTICE FOR NONCLINICAL LABORATORY STUDIES

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Subpart A--General Provisions Sec. 58.1 Scope : This part prescribes good laboratory practices for conducting nonclinical laboratory studies that support or are intended to support applications for research or marketing permits for products regulated by the FDA, including food and color additives, animal food additives, human and animal drugs, medical devices for human use, biological products, and electronic products. Compliance with this part is intended to assure the quality and integrity of the safety data.

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Sec. 58.3 Definitions: “Act”, “Test article”, “Control article”, “Nonclinical laboratory study ”, “Sponsor”, “Testing facility”, “Raw data”, “QA Unit”, “Study Director”. Nonclinical laboratory study: In vivo or in vitro experiments in which test articles are studied prospectively under laboratory conditions to determine their safety. The term does not include studies utilizing human subjects or clinical studies. The term does not include basic exploratory studies.

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Sponsor means: 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 Food and Drug Administration in support of an application for a research or marketing permit; or A testing facility, if it both initiates and actually conducts the study. Sponsor

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Raw data: it is result of original observations and activities of a nonclinical laboratory study and are necessary for the reconstruction and evaluation of the report of that study. It includes: laboratory worksheets, records, memoranda, notes, or exact copies thereof, and, photographs, microfilm or microfiche copies, computer printouts, magnetic media, including dictated observations, and recorded data from automated instruments. In the event that exact transcripts of raw data have been prepared, the exact copy or exact transcript may be substituted for the original source as raw data.

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Sec. 58.10: Applicability to studies performed under grants and contracts. When a sponsor conducting a nonclinical laboratory study utilizes the services of a consulting laboratory, contractor, or grantee, it shall notify them that the service is part of a nonclinical laboratory study and must be conducted in compliance with the provisions of this part.

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Sec. 58.15: Inspection of a testing facility. A testing facility shall permit an authorized employee of the FDA, to inspect the facility and to inspect all records and specimens required to be maintained regarding studies. Any testing facility refusing to permit inspection will be debarred/ results will not be applicable.

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Subpart B--Organization and Personnel Sec. 58.29: Personnel Individual engaged in the conduct of a nonclinical laboratory study shall have education, training, and experience, to perform the assigned functions. Current summary of training and experience and job description for each individual engaged in the conduct of a nonclinical laboratory study. There shall be a sufficient number of personnel for the timely and proper conduct of the study according to the protocol. Personnel shall take necessary personal sanitation and health precautions designed to avoid contamination of test and control articles and test systems. Personnel shall wear clothing as appropriate for the duties they perform. Such clothing shall be changed as often as necessary to prevent microbiological, radiological, or chemical contamination of test systems and test and control articles. Any individual found at any time to have an illness shall be excluded from direct contact with test systems, test and control articles and any other operation or function. All personnel shall be instructed to report any health or medical conditions that may have an adverse effect on a nonclinical laboratory study.

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Sec. 58.31 Testing facility management For each nonclinical laboratory study, testing facility management shall: Designate a study director before the study is initiated. Assure that there is a quality assurance unit. Assure that test and control articles or mixtures have been appropriately tested for identity, strength, purity, stability, and uniformity. Assure that personnel, resources, facilities, equipment, materials, and methodologies are available. Assure that personnel clearly understand the functions they are to perform. Assure that any deviations from these regulations reported by the quality assurance unit are communicated to the study director and corrective actions are taken and documented.

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Sec. 58.33 Study director For each nonclinical laboratory study, a scientist or other professional of appropriate education, training, and experience, 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. The study director shall assure that: The protocol, including any change, is approved and is followed. All experimental data, including observations of unanticipated responses of the test system are accurately recorded and verified. 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. All applicable good laboratory practice regulations are followed. All raw data, documentation, protocols, specimens, and final reports are transferred to the archives during or at the close of the study.

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Sec. 58.35 Quality assurance unit A testing facility shall have a QAU 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. QAU shall be entirely separate from and independent of the personnel engaged in the conduct of that study. The quality assurance unit shall: Maintain a copy of a master schedule sheet of all nonclinical laboratory studies conducted at the testing facility. Maintain copies of all protocols pertaining to all nonclinical laboratory studies for which the unit is responsible. Periodic inspection of each nonclinical laboratory study . Any problems found during the course of an inspection shall be brought to the attention of the study director and management immediately. Determine that no deviations from approved protocols or standard operating procedures were made without proper authorization and documentation.

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QAU….. Contd. Review the final study report to assure that that the reported results accurately reflect the raw data of the nonclinical laboratory study. Prepare and sign a statement to be included with the final study report which shall specify the dates inspections were made and findings reported to management and to the study director. The responsibilities and procedures applicable to QAU, the records maintained by QAU, and the method of indexing such records shall be in writing and shall be made available for inspection. A designated representative of the FDA shall have access to the written procedures established for the inspection.

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Subpart C—Facilities Sec. 58.41 General Each testing facility shall be of suitable size and construction to facilitate the proper conduct of nonclinical laboratory studies. Designed so that there is a degree of separation to prevent any function or activity from having an adverse effect on the study. Sec. 58.43 Animal care facilities Sufficient number of animal rooms or areas, to assure proper: (1) Separation of species or test systems, (2) isolation of individual projects, (3) quarantine of animals, and (4) routine or specialized housing of animals. Number of animal rooms or areas for biohazardous, including volatile substances, aerosols, radioactive materials, and infectious agents. Separate areas shall be provided, for the diagnosis, treatment, and control of laboratory animal diseases. These areas shall provide effective isolation for the housing of diseased animals. When animals are housed, facilities shall exist for the collection and disposal of all animal waste and refuse or for safe sanitary storage of waste before removal from the testing facility.

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Sec. 58.45 Animal supply facilities. Appropriate storage areas, for feed, bedding, supplies, and equipment. These shall be separated from areas housing the test systems and shall be protected against infestation or contamination. Perishable supplies shall be preserved by appropriate means. Sec. 58.47 Facilities for handling test and control articles. As necessary to prevent contamination or mix-ups, there shall be separate areas for: (1) Receipt and storage of the test and control articles. (2) Mixing of the test and control articles with a carrier, e.g., feed. (3) Storage of the test and control article mixtures. This is to preserve the identity, strength, purity, and stability of the articles and mixtures.

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Sec. 58.49 Laboratory operation areas . Separate laboratory space shall be provided, for the performance of the routine and specialized procedures required by nonclinical laboratory studies. Sec. 58.51 Specimen and data storage facilities. Space shall be provided for archives, limited to access by authorized personnel only, for the storage and retrieval of all raw data and specimens from completed studies. Subpart D--Equipment Sec. 58.61 Equipment design Equipment used in the generation, measurement, or assessment of data and equipment shall be of appropriate design and adequate capacity to function according to the protocol and shall be suitably located for operation, inspection, cleaning, and maintenance.

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Sec. 58.63 Maintenance and calibration of equipment. Equipment shall be adequately inspected, cleaned, tested, calibrated and/or standardized and maintained The written SOPs shall be set forth for the methods, materials, and schedules to be used in the routine inspection, cleaning, maintenance, testing, calibration, and/or standardization of equipment, Remedial action to be taken in the event of failure or malfunction of equipment should be written. Designate a person responsible for the performance of each operation. Written records shall be maintained of all inspection, maintenance, testing, calibrating and/or standardizing operations. Written records shall be kept of non-routine repairs performed on equipment as a result of failure and malfunction. Such records shall document the nature of the defect, how and when the defect was discovered, and any remedial action taken in response to the defect.

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Subpart E- - Testing Facilities Operation Sec. 58.81 Standard operating procedures A testing facility shall have standard operating procedures in writing setting forth nonclinical laboratory study methods. All deviations in a study from SOPs shall be authorized by the study director and shall be documented in the raw data. SOPs shall be established for: (1) Animal room preparation. (2) Animal care. (3) Receipt, identification, storage, handling, mixing, and method of sampling of the test and control articles. (4) Handling of animals found dead during study. (5) Necropsy or postmortem examination of animals. (6) Collection and identification of specimens. (7) Histopathology. (8) Data handling, storage, and retrieval. (9) Maintenance and calibration of equipment. (10) Transfer, proper placement, and identification of animals.

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Sec. 58.83 Reagents and solutions All reagents and solutions in the laboratory areas shall be labeled to indicate identity, titer or concentration, storage requirements, and expiration date. Deteriorated or outdated reagents and solutions shall not be used. Sec. 58.90 Animal care (a) There shall be SOPs for the housing, feeding, handling, and care of animals. (b) All newly received animals from outside sources shall be isolated and their health status shall be evaluated. (c) Animals used in the study shall be free of any disease or conditions. If, during the course of the study, the animals contract such a disease or condition, they shall be isolated. (d)These animals may be treated for disease or signs of disease provided that such treatment does not interfere with the study. (e)The diagnosis, authorizations of treatment, description of treatment, and each date of treatment shall be documented and shall be retained.

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(f)All information needed to specifically identify each animal within an animal-housing unit shall appear on the outside of that unit. (g)Adequate differentiation by space and identification shall be made to avoid any animal mix ups (h)Animal cages, racks and accessory equipment shall be cleaned and sanitized at appropriate intervals. (i)Feed and water used for the animals shall be analyzed periodically to ensure that contaminants known to be capable of interfering with the study are not present at levels above those specified in the protocol. Documentation of such analyses shall be maintained as raw data. (j) Bedding used in animal cages or pens shall not interfere with the purpose or conduct of the study and shall be changed as often as necessary to keep the animals dry and clean. (k) If any pest control materials are used, the use shall be documented. Such materials that interfere with the study shall not be used.

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Subpart F- - Test and Control Articles Sec. 58.105 Test and control article characterization (a)The test or control article shall have following information in documented evidence: identity, strength, purity, composition Methods of synthesis Fabrication marketed products will be characterized by their labeling. (b) The stability of each test or control article shall be determined : (1) Before study initiation, or (2) concomitantly according to written SOPs, which provide for periodic analysis of each batch. (c) Each storage container shall be labeled by name, chemical abstract number or code number, batch number, expiration date, storage conditions. (d) For studies of more than 4 weeks' duration, reserve samples from each batch of test and control articles shall be retained.

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Sec. 58.107 Test and control article handling Procedures shall be established for a system for the handling of the test and control articles to ensure that: (a) There is proper storage. (b) Distribution is made in a manner to avoid contamination, deterioration, or damage. (c) Proper identification is maintained throughout the distribution process. (d) The receipt and distribution of each batch is documented which includes the date and quantity of each batch distributed or returned.

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Subpart G- - Protocol for and Conduct of a Nonclinical Laboratory Study Sec. 58.120 Protocol (a) Each study shall have an approved written protocol indicating the objectives and methods for the conduct of the study. The protocol shall contain the following information: (1) 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, sub-strain, and age of the test system. (5) The procedure for identification of the test system. (6) A description of the experimental design. (7) A description of the diet used in the study as well as solvents, emulsifiers, and/or other materials used to solubilize or suspend the test or control articles before mixing with the carrier.

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(8) Dosage level, 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. (b) 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.

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Sec. 58.130 Conduct of a nonclinical laboratory study . (a) The nonclinical laboratory study shall be conducted in accordance with the protocol. (b) The test systems shall be monitored in conformity with the protocol. (c) Specimens shall be identified by test system, study, nature, and date of collection. This information shall be located in a manner that prevents error in the recording and storage of data. (d) Records from postmortem observations should be available to a pathologist when examining that specimen histopathologically. (e) Data generated during the conduct of a nonclinical laboratory study, shall be recorded directly, promptly, and legibly in ink. (f) All data entries shall be dated on the date of entry and signed or initialed by the person entering the data. (g) In automated data collection systems, the individual responsible for direct data input shall be identified at the time of data input.

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Subpart J--Records and Reports Sec. 58.185 Reporting of nonclinical laboratory study results A final report shall be prepared for each nonclinical laboratory study and shall include: (1) Name and address of the facility performing the study and the dates on which the study was initiated and completed. (2) Objectives and procedures stated in the approved protocol, including any changes in the original protocol. (3) Statistical methods employed for analyzing the data. (4) The test and control articles identified by name, chemical abstracts number or code number, strength, purity, and composition or other appropriate characteristics. (5) Stability of the test and control articles under the conditions of administration. (6) A description of the methods used.

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(7) A description of the test system used including the number of animals used, sex, body weight range, source of supply, species, strain and sub-strain, age. (8) A description of the dosage, dosage regimen, route of administration, and duration. (9) The name of the study director, the names of other scientists or professionals, and the names of all supervisory personnel, involved in the study. (10) A description of the transformations, calculations, or operations performed on the data, analysis of the data, and conclusions drawn from the analysis. (11) The signed and dated reports of each of the individual scientists or other professionals involved in the study. (12) The locations where all specimens, raw data, and the final report are to be stored. (13) The statement prepared and signed by the QAU. (b) The final report shall be signed and dated by the study director.

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Sec. 58.190 Storage and retrieval of records and data (a) All raw data, documentation, protocols, final reports, and specimens generated as a result of a nonclinical laboratory study shall be retained. (b) There shall be archives for orderly storage and expedient retrieval of all raw data, documentation, protocols, specimens, and interim and final reports. Conditions of storage shall minimize deterioration of the documents or specimens . (c) An individual shall be identified as responsible for the archives. (d) Only authorized personnel shall enter the archives. (e) Material retained or referred to in the archives shall be indexed to permit expedient retrieval.

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Sec. 58.195 Retention of records Documentation records, raw data and specimens pertaining to a nonclinical laboratory study shall be retained in the archive(s) for whichever of the following periods is shortest: A period of at least 2 years following approval by the Food and Drug Administration. A period of at least 5 years following the date on which the results of the nonclinical laboratory study are submitted to the FDA. A period of at least 2 years following the date on which the study is completed, terminated, or discontinued in cases where data is not to be submitted to the FDA. Wet specimens, samples of test or control articles, and specially prepared material, which are relatively fragile and differ markedly in stability and quality during storage, shall be retained only as long as the quality of the preparation affords evaluation.

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The master schedule sheet, copies of protocols, and records of quality assurance inspections, shall be maintained by the QAU for the period of time specified in points 1 and 2 of this section. Summaries of training and experience and job descriptions may be retained along with all other testing facility employment records for the period of time specified in points 1 and 2 of this section. Records and reports of the maintenance and calibration and inspection of equipment, shall be retained for the length of time specified in point 2 of this section. Records required by this part may be retained either as original records or as true copies such as photocopies, microfilm, microfiche, or other accurate reproductions of the original records. If a facility conducting nonclinical testing goes out of business, all raw data, documentation, and other material specified in this section shall be transferred to the archives of the sponsor of the study. The Food and Drug Administration shall be notified in writing of such a transfer.

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Subpart K--Disqualification of Testing Facilities Sec. 58.200 Purpose The purposes of disqualification are: To exclude studies that were conducted by a testing facility which has failed to comply with the requirements of the GLP regulations, and To exclude from consideration all studies completed after the date of disqualification until the facility can satisfy the Commissioner that it will conduct studies in compliance with such regulations. Disqualification, does not, however, relieve the applicant for such a permit of any obligation under any other applicable regulation to submit the results of the study to the FDA.

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Sec. 58.202 Grounds for disqualification The Commissioner may disqualify a testing facility upon finding all of the following: The testing facility failed to comply with one or more of the regulations set forth in any regulations regarding such facilities in this chapter; The noncompliance adversely affected the validity of the nonclinical laboratory studies; and Other lesser regulatory actions (e.g., warnings or rejection of individual studies) have not been or will probably not be adequate to achieve compliance with the GLP regulations.

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Sec. 58.204 Notice of and opportunity for hearing on proposed disqualification Whenever the Commissioner has observations which justify disqualification of a testing facility, he may issue to the testing facility a written notice proposing that the facility be disqualified. A hearing on the disqualification shall be conducted in accordance with the requirements for a regulatory hearing.

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Sec. 58.206 Final order on disqualification If the Commissioner, after the regulatory hearing, upon an evaluation of the administrative record of the disqualification proceeding, makes the observations suitable for disqualification, he shall issue a final order disqualifying the facility. Such order shall include a statement of the basis for that determination. Upon issuing a final order, the Commissioner shall notify (with a copy of the order) the testing facility of the action. The same procedure is true for termination of disqualification.

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Sec. 58.210 Actions upon disqualification (a) Once a testing facility has been disqualified, any study done by a testing facility before or after disqualification may be presumed to be unacceptable. (b) No nonclinical laboratory study begun by a testing facility after the date of the facility's disqualification shall be considered in support of any application for a research or marketing permit, unless the facility has been reinstated.

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Sec. 58.213 Public disclosure of information regarding disqualification Upon issuance of a final order disqualifying a testing facility, the Commissioner may notify all or any interested persons. A determination that a testing facility has been disqualified and the administrative record regarding such determination are disclosable to the public. Sec. 58.215 Alternative or additional actions to disqualification a) In addition to disqualification of a testing facility under this subpart, FDA may also refer the matter to another Federal, State, or local government law enforcement or regulatory agenies .

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Sec. 58.217 Suspension or termination of a testing facility by a sponsor The sponsor also has rights to terminate or suspend study, with reasoning and notification within 15 days. Sec. 58.219 Reinstatement of a disqualified testing facility A testing facility that has been disqualified may be reinstated if the Commissioner determines, upon an evaluation, that the facility can adequately assure that it will conduct future nonclinical laboratory studies in compliance with GLP regulations and, if any studies are currently being conducted, that the quality and integrity of such studies have not been seriously compromised. A disqualified testing facility that wishes to be so reinstated shall present in writing to the Commissioner reasons why it believes it should be reinstated and a detailed description of the corrective actions it has taken or intends to take. The Commissioner may condition reinstatement upon inspection. If a testing facility is reinstated, the Commissioner shall so notify the testing facility and all organizations and persons who were notified, of the disqualification of the testing facility. A determination that a testing facility has been reinstated is disclosable to the public.

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