Regulatory Issues in Laboratory Managment

Regulatory Issues in Laboratory Managment
1/16/2007 General Overview of Code of Federal Regulations 21 Part 58 Good Laboratory Practices Marilyn Marshall

Why GLP regulations ?

SAFETY Non-clinical safety studies are to protect the safety of the participants in clinical studies By assuring that non-clinical data is in a accordance with the GLP regulations 21 CFR 58

Subpart A: General Provisions
Chapter 1, Title 21 CFR 58 Subpart A: General Provisions Subpart B: Organization/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 nonclinical Laboratory Study Subpart J: Records and Reports Subpart K: Disqualification of Testing Facilities

Summary of Regulations 21 CFR 58
Subpart A: General Provisions 58. 1 Scope [a] This part prescribes good laboratory practices for conducting nonclinical laboratory [in vivo or in vitro] studies that support, or are intended to support, applications for research or marketing permits …….for products regulated by FDA including:

58. 1 Scope…. for products regulated by FDA including:
Subpart A: General Provisions 58. 1 Scope…. for products regulated by FDA including: food and color additives animal food additives human and animal drugs medical devices for human use biological products

Subpart A: General Provisions 58.3 GLP Definitions
Sponsor: The entity that pays the bills and holds registration. Management [UA Office of the Vice President for Research]: Appoints Study Director and assures that the testing facility is in compliance. Study Director: Legally responsible for the conduct of the study. Quality Assurance: Designated by management to perform the duties relating to quality assurance of the study.

58.3 Study: Any experiment at one or more test sites, in which a test substance is studied in a test system under laboratory conditions or in the environment to determine or help predict its effects: metabolism product performance environmental and chemical fate persistence and residue or other characteristics in humans, other living organisms or media.

58.3 Protocol: Approved, written document that clearly indicates objectives, study design and all methods to be used in conducting the study Standard operating procedures: Written, approved procedures that describe in detail standard and repetitive actions including policies Test system: the entity that the test substance is tested in or added to

58.3 Test Article: Any material or device administered to a test system Control Article: Any chemical substance or mixture, analytical standard, or material, other than a test substance, feed, or water, administered to or used in analyzing the test system to establish bases for comparison…commonly referred to as positive control or an analytical standard

Study Initiation Date: date protocol is signed by the Study Director
Subpart A: General Provisions Study Dates Study Initiation Date: date protocol is signed by the Study Director Study Completion Date: date final report is signed by the Study Director Experimental Start Date: first date the test substance is administered/ applied to the test system Experimental Completion Date: last day data are collected for the study

58.3 Specimen: any material derived from a test system for examination or analysis Sample: a portion of the test, control or reference material Batch: a specific quantity or lot of a test, control or reference material Vehicle: an agent which facilitates the mixture, dispersion or solubilization of a test substance with a carrier Carrier: the material with which the test substance is combined for administration to the test system

58.3 Archives: Area used for the orderly storage and expedient removal of all raw data, documentation, protocols, specimens, and interim and final reports.

Raw Data: Any laboratory worksheets, records, memoranda, notes, or exact copies, that are the result of original observations and activities of a study and are necessary for the reconstruction and evaluation of the report of study

58.10 Applicability to studies performed under grants and contracts:
Subpart A: General Provisions 58.10 Applicability to studies performed under grants and contracts: When a sponsor conducting a nonclinical laboratory study intended to be submitted to or reviewed by the FDA……it shall notify the consulting laboratory, contractor or grantee that the service is part of a nonclinical laboratory study that must be conducted in compliance with section 58.15….

Subpart A: General Provisions Applicability to studies performed under grants and contracts: (a) A testing facility shall permit an authorized employee of the FDA, at reasonable times in a reasonable manner to inspect to copy records …..regarding the studies with in the scope of part 58

Subpart A: General Provisions Applicability to studies performed under grants and contracts: (b) The FDA will not consider a nonclinical laboratory study in support of an application for research or marketing permit if the testing facility refuses to permit inspection.

Subpart B Organization/Personnel 58.29 Personnel
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. Training Records

(b) Each testing facility shall maintain a current summary of training and experience and job descriptions for each individual engaged in or supervising the conduct of a nonclincal laboratory study. Maintain Training Records and Job Descriptions

Training Records CV/Education summary GLP training certificates
Professional meetings attended Campus/industry certificates Chemical safely Animal Care Radiation Safety Proficiency on methods required by protocol and SOPs

(c) There shall be a sufficient number of personnel for the timely and proper conduct of the study according to the protocol. (d) Personnel shall take necessary personal sanitation and health precautions designed to avoid contamination of test and control articles and test systems. (e) Personnel engaged in a nonclinical laboratory study shall wear clothing 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.

(f) Any individual found at any time to have an illness that may adversely affect the quality and integrity of the nonclinical laboratory study shall be excluded from direct contact with the test systems, test and control articles and other operations or function that may adversely affect the study until the condition is corrected. All personnel shall be instructed to report to their immediate supervisors any health or medical conditions that may reasonably be considered to have an adverse effect on a nonclinical laboratory study.

Subpart B: Organization and Personnel
Testing Facility Management For each nonclinical laboratory study management [OVPR] shall: (a) Designate a study director before the study is initiated (b) Replace the study director promptly if it becomes necessary to do so during the study (c) Assure that there is a quality assurance unit (d) Assure that personnel, resources, facilities, equipment, materials and methods are available

Subpart B: Organization and Personnel 58. 31 ….Continuation…
(f) Assure that personnel clearly understand the functions they are to perform (g) Assure that any deviations from these regulation reported by the quality assurance unit are communicated to the study director and corrective actions are taken and documented

Management Organizational Chart, University of Arizona
21 CFR 58 Compliance

Subpart B Organization/Personnel 58.33 Study director
For each nonclincal laboratoty 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 interpretation analysis documentation reporting of results ……

…….represents the single point of study control The study director shall assure that: (a) The protocol, including any change, is approved (b) All experimental data, including observations of unanticipated responses of the test system are accurately recorded and verified.

(c) Unforeseen circumstances that may affect the quality and integrity of the nonclinical laboratory study are noted when they occur, and corrective action is taken and documented. (d) Test systems are as specified in the protocol. (e) All raw data, documentation, protocols, specimens, and final reports are transferred to the archives during or at the close of the study

Subpart B Organization/Personnel 58.35 Quality Assurance Unit
Responsible for monitoring each GLP study to assure management that the following: facilities equipment personnel methods practices records controls are in conformance with the regulation in 21 CFR 58

Quality Assurance Officer is responsible to: Maintain a copy of the Master Schedule of all studies conducted at the testing facility Maintain copies of all protocols Inspect each study at intervals to assure the integrity of the study Immediately report any problems likely to affect study integrity to management and study director

Quality Assurance Officer is responsible to: Maintain written and properly signed records of each periodic Inspection Date of Inspection Study inspected Phase or segment inspected Findings and problems Action recommended and taken to resolve existing problems Scheduled date for re-inspection

Quality Assurance Officer is responsible to: Review the final study report to assure that such report accurately: describes the methods and SOPs and that the reported results accurately reflect the raw data Prepare and sign a statement to be included with the final study report which shall specify the dates inspections were made

Examples of Quality Assurance
Assuring protocols are followed Assuring SOPs are followed Assuring deviations are documented and reported Assuring personnel are properly trained Assuring equipment calibration meets SOP requirements and documented Assuring that equipment is as specified in the protocol.

Examples of Quality Assurance
Assuring dosing/application rates as specified Assuring problems are reported to management and study director immediately Assuring study events are adequately documented Assuring management that systems are functioning as intended

Everyone bears responsibility for compliance
Management Study Director Study Facilitates Quality Assurance

Subpart C: Facilities 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 a there is a degree of separation that will prevent any function or activity from having an adverse effect on the study.

58.43 Animal Care Facilities
Subpart C: Facilities 58.43 Animal Care Facilities (a) A testing facility shall have a sufficient number of animal rooms or areas, as needed, to assure proper: isolation of individual projects quarantine of animals and routine or specialized housing of animals separation of species or test systems

Subpart C: Facilities 58.43 Animal Care Facilities (b) A testing facility shall have a number of animal rooms or areas or areas separate to ensure isolation of studies being done with test systems or test and control articles known to be bio-hazardous, including volatile substances, aerosols, radioactive materials, and infectious agents.

Subpart C: Facilities 58.43 Animal Care Facilities (c) Separate areas shall be provided, as appropriate for the diagnosis, treatment, and control of laboratory animal diseases. These areas shall provide effective isolation for the housing of animals either known or suspected of being diseased, or of being carriers of disease, from other animals.

Subpart C: Facilities 58.43 Animal Care Facilities (d) 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. Disposal facilities shall be so provided and operated as to minimize vermin infestation, odors, disease hazards, and environmental contamination.

58.47 Facilities for handling test and control articles
Subpart C: Facilities 58.47 Facilities for handling test and control articles (a) Separate areas for: Receipt and storage of the test and control articles Mixing of the test and control articles with a carrier Storage of the test and control article mixtures

58.47 Facilities for handling test and control articles
Subpart C: Facilities 58.47 Facilities for handling test and control articles (b) Storage areas for the test and/or control articles and test and control mixtures shall be separate from housing the test systems and shall be adequate to preserve the identity, strength, purity, and stability of the articles and mixtures

58.49 Laboratory Operation Areas
Subpart C: Facilities Laboratory Operation Areas Separate laboratory space shall be provided for the performance of the routine and specialized procedures required by nonclincal laboratory studies

58.51 Specimen and Data Storage
Subpart C: Facilities 58.51 Specimen and Data Storage Space shall be provided for archives, limited access by authorized personnel, for the storage and retrieval of all raw data and specimens from completed studies

Subpart D: Equipment 58.61 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 suitably located for operation, inspection, cleaning and maintenance.

58.63 Maintenance and calibration of equipment
Subpart D:Equipment 58.63 Maintenance and calibration of equipment Equipment shall be adequately inspected, cleaned and maintained. Equipment used for the generation, measurement, or assessment of data shall be adequately tested, calibrated and or standardized. SOPs shall describe methods, materials and schedules to be used in the routine inspection, cleaning, maintenance, testing, calibration …and designate the person responsible for the performance of each operation

58.63 Maintenance and calibration of equipment
Subpart D:Equipment 58.63 Maintenance and calibration of equipment (c) Written records shall be maintained of all inspection, maintenance, testing, calibration, and/or standardizing operations.

Standard Operating Procedures [SOPs]
Subpart E: Testing Facilities Section 58.81 Standard Operating Procedures [SOPs]

Standard Operating Procedures [SOPs]
Subpart E: Testing Facilities Section 58.81 Standard Operating Procedures [SOPs] (a) A testing facility shall have standard operating procedures in writing setting forth nonclinical laboratory study methods that management is satisfied are adequate to insure the quality and integrity of the data generated in the course of study. All deviations in a study from the SOPs shall be authorized by the study director and shall be documented in the raw data. Significant changes in established SOPs shall be properly authorized in writing by the management.

Subpart E: Testing Facilities
58.81 SOPs…. (c) Each laboratory area shall have immediately available laboratory manuals and SOPs relative to the laboratory procedures being performed. Published literature may be used as a supplement to SOPs. (d) A historical file of SOPs and all revisions thereof, including the dates of such revisions, shall be maintained.

58.83 Reagents and Solutions
Subpart E: Testing Facilities 58.83 Reagents and Solutions All reagents and shall be labeled to indicate: identity titer/concentration storage requirements expiration date

58.83 Reagents and Solutions
Subpart E: Testing Facilities 58.83 Reagents and Solutions Deteriorated or outdated reagents and solutions shall not be used

Subpart E: Testing Facilities
Animal Care

58.105 Test and Control Article Characterization
Subpart F: Test and Control Articles Test and Control Article Characterization (a) The identity, strength, purity, and composition or other characteristics which will define the test or control article shall be determined for each batch……and shall be documented (b) The stability of each test or control article shall be determined by the testing facility or by the sponsor….. (c) Each storage container for a test or control article shall be labeled by name, chemical substance, expiration date, …..

58.105 Test and Control Article Characterization
Subpart F: Test and Control Articles Test and Control Article Characterization (d) For studies of more than 4 weeks duration, reserve samples from each batch of test or control articles shall be retained….

(a) Each study shall have an approved written protocol
Subpart G: Protocol for and Conduct of a nonclinical Laboratory Study Protocol…. (a) Each study shall have an approved written protocol Descriptive title and statement of the purpose of the study Identification of the test and control articles by name, chemical abstract number, or code number Name of the sponsor and the name and address of the testing facility at which the study is being conducted

Subpart G: Protocol for and Conduct of a nonclinical Laboratory Study
Number, body weight range, sex, source of supply, species, strain, substrain, and age of the test system…….cell line, original source, passage number Procedure for identification of the test system A description of the experimental design A description and/or identification 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.

The type and frequency of tests, analyses, and measurements to be made
Subpart G: Protocol for and Conduct of a nonclinical Laboratory Study Protocol Each dosage level expressed in milligrams per kilogram of body weight, or other appropriate units of the test control article to be administered and the method of administration The type and frequency of tests, analyses, and measurements to be made The date of approval of the protocol by the sponsor and dated signature of the study director A statement of the proposed statistical methods All changes to the approved protocol shall be documented, signed by study director and dated maintained with the protocol

( a) study shall be conducted in accordance with the protocol.
Subpart G: Protocol for and Conduct of a nonclinical Laboratory Study Conduct ( a) study shall be conducted in accordance with the protocol. (b) test systems shall be monitored in conformity with protocol (c) specimens shall be identified by test system, study, nature, and date of collection. This information must be located on the specimen container or accompany the specimen in a manner that precludes error in the recording and storage of data.

Subpart G: Protocol for and Conduct of a nonclinical Laboratory Study
(d) records of gross findings for a specimen from postmortem observations should be available to a pathologist when examing that specimen histopathologically. (e) All data generated during the conduct of a study except those that are generated by automated data collection systems, shall be: > recorded directly > promptly > and legibly in ink

Conduct All data entries shall be dated on the date of entry and signed or initialed by the person entering the data Any change in entries shall be made so as not to obscure the original entry and shall indicate the reason for such a change and shall be dated and signed or identified at the time of change. Subpart G: Protocol for and Conduct of a nonclinical Laboratory Study

Laboratory/Study Documentation :
Write neatly Use a pen with ink that does not smear Make sure all boxes, and lines are completed on checklists….if there is no information, enter n/a for “not applicable” or draw a line through empty line/box. Always sign and/or initial and date entries For documenting dates…be sure to include the year For clarity use military time or AM/PM

Raw Data/Documentation Promptly
Recorded as generated Take forms to the field/lab No keeping several measurements “in your head” No filling out data sheets at the end of the day or “when time allows” ….real time data!!

Raw Data/Documentation Directly (original)
Onto appropriate forms Into appropriate logs First entry is the RAW data

Raw Data/Documentation Legibly
Understandable – can a third party figure it out? If it can’t be read, it is not legible If you are sloppy, slow down and print Do not “scrunch” data Don’t write on backs of pages Don’t write in borders or margins, use additional paper

Raw Data/Documentation Other considerations
In permanent medium (INK) Color not specific; must be indelible Entries signed/dated at the time of entry Data corrections in compliance with GLP Must not obscure original (one line through) Reason given (error code) Signed and dated by person making correction

Raw Data/Documentation Maintained in an organized manner
- Data collection forms All data points required by the protocol collected Values of lab analyses recorded on a record sheet or attached Normal reference values included

Corrections/updates to documentation (other than SOPs) may be made at any time as long as each….. > is initialed > is dated > includes a short explanation as to why the information was not included before

Legibility ….must be able to read Identifiably….who did the work Retrievability ….can find the raw data Documentation should allow you to be able to reconstruct the study for legal and regulatory purposes if needed

58.185 Reporting of nonclinical laboratory study results
(a) Final report Name and address of the facility performing the study and the dates on which the study was initiated and completed Objectives and procedures stated in the approved protocol, including any changes in the original protocol Statistical methods employed Subpart J: Records and Reports

(a) Final report The test and control articles identified by name, chemical code number, strength, purity, and composition or other appropriate characteristics Stability of the test and control articles under the conditions of administration A description of the method used Subpart J: Records and Reports

(a) Final report A description of the test system used including the number of animals used, sex, body weight range, source of supply, species, strain, age and procedure used for identification A description of the dosage, dosage regimen, route of administration, and duration. Subpart J: Records and Reports

(a) Final report A description of all circumstances that may have effected the quality or integrity of the data The name of the study director, the names of other scientists or professionals, and the names of all supervisory personnel, involved in the study Subpart J: Records and Reports

(a) Final report A description of the transformations, calculations or operations performed on the data, a summary and analysis of the data, and a statement of the conclusions drawn from the analysis Locations where all specimens, raw data, and the final report are to be stored The statement prepared and signed by the quality assurance unit Subpart J: Records and Reports

(b) Final report shall be signed and dated by the study director (c) Corrections or additions to a final report shall be in the form of an amendment by the study director Subpart J: Records and Reports

58.190 Storage and retrieval of records and data
(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 archives Subpart J: Records and Reports

(a) All raw data, documentation, protocols, final reports and specimens…. (except wet specimens of blood, urine, feces and biological fluids….) generated as a result of a nonclinical laboratory study shall be retained.. Subpart J: Records and Reports

(d) Only authorized personnel shall enter the archives (e) Material retained or referred to in the archives shall be indexed to permit expedient retrieval Subpart J: Records and Reports

Different interpretations as to time period….
Retention of records Different interpretations as to time period…. (1) A period of a least 2 years following the date on which an application for a research or marketing permit, in support of which the results of the nonclinical laboratory study were submitted, is approved by the FDA (2) A period of at least 5 years for IND’s (Investigational New Drug) IDE’s (Investigational Device Exemptions Subpart J: Records and Reports

Retention of records (3) In other situations where the study does not result in submission of the study…. at least 2 years following the date on which the study was completed, terminated or discontinued Subpart J: Records and Reports

Records of maintenance, and calibration
Retention of records (c) Wet specimens …. samples of test or control articles shall be retained only as long as the quality of the preparation affords evaluation. Master schedule sheet, copies of protocols and records of QA inspections shall be maintained by the QAU Summaries of training and experience and job descriptions shall be retained…. Records of maintenance, and calibration Subpart J: Records and Reports

Retention of records (g) 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 (h) If a facility conducting testing goes out of business, all raw data, documentation, and other material shall be transferred to the archives of the sponsor of the study. FDA should be notified of transfer. Subpart J: Records and Reports

Benefits of GLP… SOPs as training tools
SOPs for reproducible methodogies Record of equipment maintenance and use Record of reagent lot #s or instrument operating parameters that provide traceability, and verification of study results Easier preparation of final reports

Life after GLPs WCAC All procedures are now written down and in notebooks. The procedures are done consistently and records are uniformly kept by everyone. All procedures done with known standardized and current chemicals. It is much easier to train new students and personnel with written procedures. Equipment is maintained on a yearly basis. Facility has maintained GLPs, throughout, even though only one room is used for the FDA project.

Life after GLPs Main Campus We survived.
All procedures are now written in a consistent form and easily found in notebooks. Inconsistencies of procedures have been corrected and everyone is doing procedures uniformly. Maintenance records of equipment and chemical/ stain inventories are readily available. Everyone is more aware of procedures, keeping records, etc., even in the areas not brought up to GLP standards.

Overall Advantages As the decline in research funding continues, it is assumed being a GLP laboratory will give us an edge over other non-GLP research facilities. Personnel CVs are always current. Equipment is better maintained. Procedures are known to be done the same by everyone and procedural questions are fewer.

responsibility for compliance
Everyone bears responsibility for compliance Management Study Director Study Facilitates Quality Assurance

Document That You Did It
Plan What You Do Do What You Plan Document That You Did It

If it is not written down…..
It did not Happen!!! Good Practices = Good Science

Quality……. “ Quality is never an accident; it is always the result of high intention, sincere effort, intelligent direction, and skillful execution

Regulatory Issues in Laboratory Managment

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