2. Date(s) of Inspection:
3. Application No. (if applicable):
4. Application Sponsor (if any):
5. Location where testing performed:
a. Clinical Facility Name: Address:
c. Central File No.:
d. Analytical Facility Name:
g. Central File No.:
6. Responsible Official (Recipient of Notice of Inspection): a. Name and Title:
7. Person receiving FDA-483 (if issued): a. Name and Title:
8. Drug under study:
a. Generic Name:
b. Trade Name:
c. Dosage Form:
9. Number of subjects in clinical test:
10. Status of clinical testing:
a. Date Started:
b. Completion Date:
11. Sample Collection Sample Lot #-
12. FDA Investigator(s):
In the 1970s, FDA inspections of nonclinical laboratories revealed that some studies submitted in support of the safety of regulated products had not been conducted in accord with acceptable practice, and that accordingly data from such studies was not always of the quality and integrity to assure product safety. As a result of these findings, FDA promulgated the GLP Regulations, 21 CFR Part 58, on December 22, 1978 (43 FR 59986). The regulations became effective June 1979. The regulations establish standards for the conduct and reporting of nonclinical laboratory studies and are intended to assure the quality and integrity of safety data submitted to the FDA.
The FDA relies on documented adherence to GLP requirements by nonclinical laboratories in judging the acceptability of safety data submitted in support of research and/or marketing permits. The FDA has implemented this program of regular inspections and data audits to monitor laboratory compliance with the GLP requirements.
The objective of this program is
1. To verify the quality and integrity of data submitted in a research or marketing application.
2. To inspect (approximately every two years) nonclinical laboratories conducting safety studies that are intended to support applications for research or marketing of regulated products.
3. To audit safety studies and determine the degree of compliance with GLP regulations. a. Types of Inspections i. Surveillance Inspections. Surveillance inspections are periodic, routine determinations of a laboratory's compliance with GLP regulations. These inspections include a facility inspection and audits of ongoing and/or recently completed studies.
ii. Directed Inspections
- Directed inspections are assigned to achieve a specific purpose, such as:
- Verifying the reliability, integrity, and compliance of critical safety studies being reviewed in support of pending applications.
- Investigating issues involving potentially unreliable safety data and/or viola-tive conditions brought to the FDA's attention.
- Reinspecting laboratories previously classified OAI (usually within six months after the firm responds to a Warning Letter).
- Verifying the results from third party audits or sponsor audits submitted to the FDA for consideration in determining whether to accept or reject questionable or suspect studies.
1. The investigator will determine the current state of GLP compliance by evaluating the laboratory facilities, operations, and study performance.
2. Organization chart—If the facility maintains an organization chart, obtain a current version of the chart for use during the inspection and submit it in the EIR.
3. Facility floor-plan diagram—Obtain a diagram of the facility. The diagram may identify areas that are not used for GLP activities. If it does not, request that appropriate facility personnel identify any areas that are not used for GLP activities. Use during the inspection and submit it in the EIR.
4. Master schedule sheet—Obtain a copy of the firm's master schedule sheet for all studies listed since the last GLP inspection or last two years and select studies as defined in 21 CFR 58.3(d). If the inspection is the first inspection of the facility, review the entire master schedule. If studies are identified as non-GLP, determine the nature of several studies to verify the accuracy of this designation. See 21 CFR 58.1 and 58.3(d). In contract laboratories determine who decides if a study is a GLP study.
5. Identification of studies a. Directed Inspections—Inspection assignments will identify studies to be audited.
b. Surveillance Inspections—Inspection assignments may identify one or more studies to be audited. If the assignment does not identify a study for coverage, or if the referenced study is not suitable to assess all portions of current GLP compliance, the investigator will select studies as necessary to evaluate all areas of laboratory operations. When additional studies are selected, first priority should be given to FDA studies for submission to the assigning Center.
6. Ongoing studies—Obtain a copy of the study protocol and determine the schedule of activities that will be underway during the inspection. This information should be used to schedule inspections of ongoing laboratory operations, as well as equipment and facilities associated with the study. If there are no activities underway in a given area for the study selected, evaluate the area based on ongoing activities.
7. Completed studies—The data audit should be carried out as outlined in Part III. If possible, accompany laboratory personnel when they retrieve the study data to assess the adequacy of data retention, storage, and retrieval as described in Part III.
The facility inspection should be guided by the GLP regulations. The following areas should be evaluated and described as appropriate.
1. Organization and personnel (21 CFR 58.29, 58.31, 58.33)
a. Purpose—To determine whether the organizational structure is appropriate to ensure that studies are conducted in compliance with GLP regulations, and to determine whether management, study directors, and laboratory personnel are fulfilling their responsibilities under the GLPs.
b. Management responsibilities (21 CFR 58.31)—Identify the various organizational units, their role in carrying out GLP study activities, and the management responsible for these organizational units. This includes identifying personnel who are performing duties at locations other than the test facility and identifying their line of authority. If the facility has an organization chart, much of this information can be determined from the chart.
2. Determine if management has procedures for assuring that the responsibilities in 58.31 can be carried out. Look for evidence of management involvement, or lack thereof, in the following areas:
a. Assigning and replacing study directors.
b. Control of study director workload (use the Master Schedule to assess workload).
c. Establishment and support of the quality assurance unit (QAU), including assuring that deficiencies reported by the QAU are communicated to the study directors and acted upon.
d. Assuring that test and control articles or mixtures are appropriately tested for identity, strength, purity, stability, and uniformity.
e. Assuring that all study personnel are informed of and follow any special test and control article handling and storage procedures.
f. Providing required study personnel, resources, facilities, equipment, and materials.
g. Reviewing and approving protocols and SOPs.
h. Providing GLP or appropriate technical training.
3. Personnel (21 CFR 58.29)—Identify key laboratory and management personnel, including any consultants or contractors used, and review personnel records, policies, and operations to determine if:
a. Summaries of training and position descriptions are maintained and are current for selected employees.
b. Personnel have been adequately trained to carry out the study functions that they perform.
c. Personnel have been trained in GLPs.
d. Practices are in place to ensure that employees take necessary health precautions, wear appropriate clothing, and report illnesses to avoid contamination of the test and control articles and test systems.
4. If the firm has computerized operations, determine the following:
a. Who was involved in the design, development, and validation of the computer system?
b. Who is responsible for the operation of the computer system, including inputs, processing, and output of data?
c. Whether computer system personnel have training commensurate with their responsibilities, including professional training and training in GLPs?
d. Whether some computer system personnel are contractors who are present on-site fulltime, or nearly full-time. The investigation should include these contractors as though they were employees of the firm. Specific inquiry may be needed to identify these contractors, as they may not appear on organization charts.
e. Interview and observe personnel using the computerized systems to assess their training and performance of assigned duties.
5. Study director (21 CFR 58.33)
a. Assess the extent of the study director's actual involvement and participation in the study. In those instances when the study director is located off-site, review any correspondence/records between the testing facility management and QAU and the off-site study director. Determine that the study director is being kept immediately apprised of any problems that may affect the quality and integrity of the study.
b. Assess the procedures by which the study director:
c. Assures the protocol and any amendments have been properly approved and are followed.
d. Assures that all data are accurately recorded and verified.
e. Assures that data are collected according to the protocol and SOPs.
f. Documents unforeseen circumstances that may affect the quality and integrity of the study and implements corrective action.
g. Assures that study personnel are familiar with and adhere to the study protocol and SOPs.
h. Assures that study data are transferred to the archives at the close of the study.
6. EIR Documentation and Reporting—Collect exhibits to document deficiencies. This may include SOPs, organizational charts, position descriptions, and CVs, as well as study-related memos, records, and reports for the studies selected for review. The use of outside or contract facilities must be noted in the EIR. The assigning Center should be contacted for guidance on inspection of these facilities.
a. Purpose: To determine if the test facility has an effective, independent QAU that monitors significant study events and facility operations, reviews records and reports, and assures management of GLP compliance.
8. QAU Operations—[21 CFR 58.35(b-d)]—Review QAU SOPs to assure that they cover all methods and procedures for carrying out the required QAU functions, and confirm that they are being followed. Verify that SOPs exist and are being followed for QAU activities including, but not limited to, the following:
a. Maintenance of a master schedule sheet.
b. Maintenance of copies of all protocols and amendments.
c. Scheduling of its in-process inspections and audits.
d. Inspection of each nonclinical laboratory study at intervals adequate to assure the integrity of the study, and maintenance of records of each inspection.
e. Immediately notify the study director and management of any problems that are likely to affect the integrity of the study.
f. Submission of periodic status reports on each study to the study director and management.
g. Review of the final study report.
h. Preparation of a statement to be included in the final report that specifies the dates inspections were made and findings reported to management and to the study director.
a. Verify that, for any given study, the QAU is entirely separate from and independent of the personnel engaged in the conduct and direction of that study. Evaluate the time QAU personnel spend in performing in-process inspection and final report audits.
Determine if the time spent is sufficient to detect problems in critical study phases and if there are adequate personnel to perform the required functions. b. Note: The investigator may request the firm's management to certify in writing that inspections are being implemented, performed, documented, and followed-up in accordance with this section [See 58.35(d)].
10. EIR Documentation and reporting—Obtain a copy of the master schedule sheet dating from the last routine GLP inspection or covering the past two years. If the master schedule is too voluminous, obtain representative pages to permit headquarters review. When master schedule entries are coded, obtain the code key. Deficiencies should be fully reported and documented in the EIR. Documentation to support deviations may include copies of QAU SOPs, list of QAU personnel, their curriculum vitae (CVs) or position descriptions, study-related records, protocols, and final reports.
11. Facilities (21 CFR 58.41-51)
a. Purpose: Assess whether the facilities are of adequate size and design.
b. Facility inspection i. Review environmental controls and monitoring procedures for critical areas (i.e., animal rooms, test article storage areas, laboratory areas, handling of bio-hazardous material, etc.) and determine if they appear adequate and are being followed.
ii. Review the SOPs that identify materials used for cleaning critical areas and equipment, and assess the facility's current cleanliness.
iii. Determine whether there are appropriate areas for the receipt, storage, mixing, and handling of the test and control articles.
iv. Determine whether separation is maintained in rooms where two or more functions requiring separation are performed.
v. Determine that computerized operations and archived computer data are housed under appropriate environmental conditions (e.g., protected from heat, water, electromagnetic forces).
12. EIR documentation and reporting—Identify which facilities, operations, SOPs, etc., were inspected. Only significant changes in the facility from previous inspections need be described. Facility floor plans may be collected to illustrate problems or changes. Document any conditions that would lead to contamination of test articles or to unusual stress of test systems.
13. Equipment (21 CFR 58.61-63)
a. Purpose: To assess whether equipment is appropriately designed and of adequate capacity and is maintained and operated in a manner that ensures valid results.
b. Equipment Inspection—Assess the following:
i. The general condition, cleanliness, and ease of maintenance of equipment in various parts of the facility.
ii. The heating, ventilation, and air conditioning system design and maintenance, including documentation of filter changes and temperature/humidity monitoring in critical areas.
iii. Whether equipment is located where it is used and that it is located in a controlled environment, when required.
iv. Nondedicated equipment for preparation of test and control article carrier mixtures is cleaned and decontaminated to prevent cross contamination.
v. For representative pieces of equipment check the availability of the following:
- SOPS and/or operating manuals.
- Maintenance schedule and log.
- Standardization/calibration procedure, schedule, and log.
- Standards used for calibration and standardization.
vi. For computer systems, assess that the following procedures exist and are documented:
- Validation study, including validation plan and documentation of the plan's completion.
- Maintenance of equipment, including storage capacity and backup procedures.
- Control measures over changes made to the computer system, which include the evaluation of the change, necessary test design, test data, and final acceptance of the change.
- Evaluation of test data to assure that data are accurately transmitted and handled properly when analytical equipment is directly interfaced to the computer..
- Procedures for emergency backup of the computer system (e.g., backup battery system and data forms for recording data in the event of a computer failure or power outage).
14. EIR documentation and reporting—The EIR should list which equipment, records, and procedures were inspected and the studies to which they are related. Detail any deficiencies that might result in contamination of test articles, uncontrolled stress to test systems, and/or erroneous test results.
15. Testing facility operations (21 CFR 58.81)
a. Purpose: To determine if the facility has established and follows written SOPs necessary to carry out study operations in a manner designed to ensure the quality and integrity of the data.
b. SOP Evaluation i. Review the SOP index and representative samples of SOPs to ensure that written procedures exist to cover at least all of the areas identified in 58.81(b).
ii. Verify that only current SOPs are available at the personnel workstations.
iii. Review key SOPs in detail and check for proper authorization signatures and dates, and general adequacy with respect to the content (i.e., SOPs are clear, complete, and can be followed by a trained individual).
iv. Verify that changes to SOPs are properly authorized and dated and that a historical file of SOPs is maintained.
v. Ensure that there are procedures for familiarizing employees with SOPs.
vi. Determine that there are SOPs to ensure the quality and integrity of data, including input (data checking and verification), output (data control), and an audit trail covering all data changes.
vii. Verify that a historical file of outdated or modified computer programs is maintained. If the firm does not maintain old programs in digital form, ensure that a hard copy of all programs has been made and stored.
viii. Verify that SOPs are periodically reviewed for current applicability and that they are representative of the actual procedures in use.
ix. Review selected SOPs and observe employees performing the operation to evaluate SOP adherence and familiarity. EIR Documentation and Reporting-Submit SOPs, data collection forms, and raw data records as exhibits that are necessary to support and illustrate deficiencies.
16. Reagents and solutions (21 CFR 58.83)
a. Purpose: To determine that the facility ensures the quality of reagents at the time of receipt and subsequent use.
i. Review the procedures used to purchase, receive, label, and determine the acceptability of reagents and solutions for use in the studies.
ii. Verify that reagents and solutions are labeled to indicate identity, titer or concentration, storage requirements, and expiration date.
iii. Verify that for automated analytical equipment, the profile data accompanying each batch of control reagents are used.
iv. Check that storage requirements are being followed.
17. Test and control articles (21 CFR 58.105-113)
a. Purpose: To determine that procedures exist to assure that test and control articles and mixtures of articles with carriers meet protocol specifications throughout the course of the study, and that accountability is maintained.
b. Characterization and Stability of Test Articles (21 CFR 58.105)—The responsibility for carrying out appropriate characterization and stability testing may be assumed by the facility performing the study or by the study sponsor. When test article characterization and stability testing is performed by the sponsor, verify that the test facility has received documentation that this testing has been conducted.
c. Verify that procedures are in place to ensure that i. The acquisition, receipt and storage of test articles, and means used to prevent deterioration and contamination are as specified.
ii. The identity, strength, purity, and composition (i.e., characterization) to define the test and control articles are determined for each batch and are documented.
iii. The stability of test and control articles is documented.
iv. The transfer of samples from the point of collection to the analytical laboratory is documented.
v. Storage containers are appropriately labeled and assigned for the duration of the study.
vi. Reserve samples of test and control articles for each batch are retained for studies lasting more than four weeks.
d. Test and control article handling (21 CFR 58.107). Determine that there are adequate procedures for:
i. Documentation for receipt and distribution.
ii. Proper identification and storage.
iii. Precluding contamination, deterioration, or damage during distribution.
iv. Inspect test and control article storage areas to verify that environmental controls, container labeling, and storage are adequate.
v. Observe test and control article handling and identification during the distribution and administration to the test system.
vi. Review a representative sample of accountability records and, if possible, verify their accuracy by comparing actual amounts in the inventory. For completed studies verify documentation of final test and control article reconciliation.
18. Protocol and conduct of nonclinical laboratory study (21 CFR 58.120-130)
a. Purpose: To determine if study protocols are properly written and authorized, and that studies are conducted in accordance with the protocol and SOPs.
b. Study protocol (21 CFR 58.120)
i. Review SOPs for protocol preparation and approval and verify they are followed.
ii. Review the protocol to determine if it contains required elements.
iii. Review all changes, revisions, or amendments to the protocol to ensure that they are authorized, signed, and dated by the study director.
iv. Verify that all copies of the approved protocol contain all changes, revisions, or amendments.
19. Conduct of the nonclinical laboratory study (21 CFR 58.130). Evaluate the following laboratory operations, facilities, and equipment to verify conformity with protocol and SOP requirements for:
a. Test system monitoring.
b. Recording of raw data (manual and automated).
c. Corrections to raw data (corrections must not obscure the original entry and must be dated, initialed, and explained).
d. Randomization of test systems.
e. Collection and identification of specimens.
f. Authorized access to data and computerized systems.
20. Records and reports (21 CFR 58.185-195)
a. Purpose: To assess how the test facility stores and retrieves raw data, documentation, protocols, final reports, and specimens.
b. Reporting of Study Results (21 CFR 58.185)—Determine if the facility prepares a final report for each study conducted.
21. Storage and retrieval of records and data (21 CFR 58.190)
a. Verify that raw data, documentation, protocols, final reports, and specimens have been retained.
b. Identify the individual responsible for the archives. Determine if delegation of duties to other individuals in maintaining the archives has occurred.
c. Verify that archived material retained or referred to in the archives is indexed to permit expedient retrieval. It is not necessary that all data and specimens be in the same archive location. For raw data and specimens retained elsewhere, the archives index must make specific reference to those other locations.
d. Verify that access to the archives is controlled and determine that environmental controls minimize deterioration.
e. Ensure that there are controlled procedures for adding or removing material. Review archive records for the removal and return of data and specimens. Check for unexplained or prolonged removals.
f. Determine how and where computer data and backup copies are stored, that records are indexed in a way to allow access to data stored on electronic media, and that environmental conditions minimize deterioration.
g. Determine to what electronic media such as tape cassettes or ultra high capacity portable discs the test facility has the capacity of copying records in electronic form. Report names and identifying numbers of both copying equipment type and electronic medium type to enable agency personnel to bring electronic media to future inspections for collecting exhibits.
22. Data audit. In addition to the procedures outlined above for evaluating the overall GLP compliance of a firm, the inspection should include the audit of at least one completed study. Studies for audit may be assigned by the Center or selected by the investigator as described in Part III. The audit will include a comparison of the protocol (including amendments to the protocol), raw data, records, and specimens against the final report to substantiate that protocol requirements were met and that findings were fully and accurately reported. For each study audited, the study records should be reviewed for quality to ensure that data are a. Attributable—the raw data can be traced, by signature or initials and date to the individual observing and recording the data. Should more than one individual observe or record the data, that fact should be reflected in the data.
b. Legible—the raw data are readable and recorded in a permanent medium. If changes are made to original entries, the changes:
i. Must not obscure the original entry.
ii. Indicate the reason for change.
iii. Must be signed or initialed and dated by the person making the change.
c. Contemporaneous-the raw data are recorded at the time of the observation.
d. Original-the first recording of the data.
e. Accurate—the raw data are true and complete observations. For data entry forms that require the same data to be entered repeatedly, all fields should be completed or a written explanation for any empty fields should be retained with the study records.
23. General a. Determine if there were any significant changes in the facilities, operations, and QAU functions other than those previously reported.
b. Determine whether the equipment used was inspected, standardized, and calibrated prior to, during, and after use in the study. If equipment malfunctioned, review the remedial action, and ensure that the final report addresses whether the malfunction affected the study.
c. Determine if approved SOPs existed during the conduct of the study. Compare the content of the protocol with the requirements in 21 CFR. Review the final report for the study director's dated signature and the QAU statement as required in 21 CFR 58.35(b)(7).
24. Protocol versus final report—Study methods described in the final report should be compared against the protocol and the SOPs to confirm those requirements were met.
25. Final report versus raw data. The audit should include a detailed review of records, memorandum, and other raw data to confirm that the findings in the final report completely and accurately reflect the raw data. Representative samples of raw data should be audited against the final report.
26. Samples. Collection of samples should be considered when the situation under audit or surveillance suggests that the facility had, or is having, problems in the area of characterization, stability, storage, contamination, or dosage preparation.
27. Inspectional observations. An FDA 483 listing inspectional observations will be issued under this program. Findings should not be listed on the FDA 483 if in the opinion of the field investigator:
a. The findings are problems that have been observed and corrected by the firm through its internal procedures.
b. The findings are minor and are one-time occurrences that have no impact on the firm's operations, study conduct, or data integrity.
c. Findings that are not considered significant enough to be listed on the FDA 483 may be discussed with the firm's management. Such discussions must be reported in the EIR. Analyzing Laboratories.
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