In order to standardize the quality management norms for non-clinical drug research (GLP) on-site inspection work and improve inspection quality, the "Key Points and Determination Principles for GLP Inspection" have been formulated in accordance with relevant requirements such as the "Drug Administration Law of the People's Republic of China", "Quality Management Norms for Non-clinical Drug Research", and "Management Measures for Certification of Quality Management Norms for Non-clinical Drug Research".
1. Purpose
Through on-site inspections of the organizational structure and personnel, quality assurance, facilities, experimental systems, instruments and equipment, experimental materials, test substances and control samples, standard operating procedures (SOP), implementation of research work, data archives, computerized systems, etc., of GLP certification applicant institutions or GLP institutions (hereinafter referred to as institutions), evaluate whether the operation of the institution's quality management system and the implementation of research projects meet GLP requirements.
2. Scope of Application
1. These inspection key points and determination principles apply to GLP certification on-site inspections and GLP supervision on-site inspections organized and implemented by the Food and Drug Audit and Inspection Center of the National Medical Products Administration (hereinafter referred to as the Inspection Center).
2. Provincial drug supervision and administration bureaus can refer to these inspection key points and determination principles for daily supervision inspections.
3. Depending on the type of application and the focus of supervision inspections, on-site inspections may apply the corresponding parts of the inspection key points.
3. Inspection Key Points
(1) Organizational Structure and Personnel
Confirm that the institution has a complete organizational management system, sufficient trained and qualified personnel, and that they comply with GLP requirements in their work. This part of the inspection key points includes but is not limited to:
1. The institution has a complete organizational management system, equipped with a responsible person (FM), quality assurance department, and corresponding staff, with reasonable departmental settings and clear division of responsibilities.
2. The institution has staff that match the non-clinical safety evaluation research (hereinafter referred to as research) being conducted; staff possess qualifications, experience, and capabilities that match their positions, have received relevant GLP and skills training, and carry out work according to GLP, SOP, and experimental protocols.
3. The institution formulates and implements personnel training SOPs, providing GLP and relevant skills training for staff. Staff can only take up their positions after passing training assessments.
4. The institution maintains and regularly updates personnel archive materials. Personnel archive materials should include at least job descriptions, educational background, work experience, training records, and qualifications. Training records should include at least GLP training and SOP and skills training related to their positions.
5. The institution formulates and implements personnel health examination regulations, conducts regular health examinations, and evaluates the results. If personnel have health issues that affect research quality, relevant measures are taken to prevent their participation in work that may impact the research.
6. The FM can fulfill their responsibilities and is fully responsible for the institution's operational management.
7. The study director (SD) has qualifications and experience that match the research project they are responsible for, can fulfill their responsibilities, and is fully responsible for the implementation and quality of the research project. Only one SD is allowed for a research project at the same time. Changes to the SD are made according to prescribed procedures and recorded.
(2) Quality Assurance (QA)
Confirm that the institution's QA department and QA personnel can independently perform QA duties and have effectively inspected the operation of the institution's quality management system and the implementation of research projects. This part of the inspection key points includes but is not limited to:
1. The institution has an independent QA department; QA personnel do not participate in the implementation of specific research projects or undertake other work that may affect the independence of QA work.
2. The qualifications, experience, and training of the QA department head and QA personnel meet the requirements for QA positions and possess corresponding work capabilities.
3. Maintain copies of the experimental protocols and changes for ongoing research projects, current SOP copies, and timely obtain copies of the master schedule.
4. Formulate a quality assurance plan, designate executing personnel, and carry out inspections based on research, facilities, and processes according to the plan:
4.1 Each research project has an inspection plan and conducts research-based inspections. The frequency of inspections can confirm that the implementation of the research project meets GLP requirements, and the scope of inspections can cover key stages of the research project. Review the experimental protocol and summary report of each research project, and sign the quality assurance statement. Quality assurance inspections retain process records and reports. The quality assurance statement includes research project information, inspection type, research phase and time of inspection, inspection results reported to FM, SD, and principal investigator (PI, if multi-site research) dates, etc.; for modifications or supplements to approved summary reports, QA personnel review the modifications or supplements and sign the quality assurance statement.
4.2 Regularly conduct facility-based inspections to review the GLP operational management status of the institution. For example: the use, maintenance, validation, or confirmation of instruments and equipment (including computerized systems), personnel training, environmental monitoring, data archiving, and the use and management of test substances and control samples, SOP management, etc. The scope and frequency of inspections should be sufficient to confirm that the institution's operations meet GLP requirements.
4.3 Regularly conduct process-based inspections, which should specify the specific inspection content and frequency (if applicable).
5. Timely report inspection results in writing to FM, SD, and other relevant personnel; promptly follow up on issues identified during inspections and verify rectification results; in multi-site research, QA personnel from different research sites will report inspection results simultaneously to the FM, SD, and QA personnel of the main research site; the QA of the main research site confirms the GLP compliance of the research work undertaken by the sub-research sites.
6. Retain various inspection-related records and reports and archive them in a timely manner. Inspection records and reports should reflect information such as inspection type, inspectors, inspection date, inspection content, identified issues, feedback from SD or relevant personnel on issues, and QA personnel's verification of rectification results, and FM's confirmation of the inspection report.
7. Review the institution's SOP.
(3) Facilities
Confirm that the institution has facilities that match the research applied for and that environmental conditions meet requirements; appropriate measures are in place to prevent confusion or cross-contamination. This part of the inspection key points includes but is not limited to:
1. The facility layout is reasonable, operationally normal, and appropriately scaled, suitable for the research applied for.
2. Necessary functional divisions and separations are in place to avoid interference between test substances and control samples, experimental systems, feed, samples, specimens, etc.
3. The institution has animal husbandry and auxiliary facilities that are appropriate for the level and species of experimental animals used in the research (e.g., washing facilities, animal isolation and quarantine or treatment facilities, storage facilities for bedding, cages, and other experimental supplies, etc.), and has a valid "Experimental Animal Use License"; there are appropriate control and monitoring measures to ensure that environmental conditions (e.g., temperature, humidity, air cleanliness, ventilation, and lighting, etc.) meet requirements and corresponding monitoring records are maintained.
4. Different species of experimental animals have effective isolation measures; experimental animals of the same species that must be kept in the same breeding room for different research projects have appropriate separation and labeling measures.
5. There are functional testing areas that are appropriate for the applied research; environmental control and monitoring measures, as well as personnel protection measures, meet the requirements for the environment and personnel health protection in the functional testing area.
6. The reception, storage, preparation, and post-preparation storage of test substances and control samples have independent rooms or areas with necessary isolation measures; appropriate control and monitoring measures are in place to ensure that environmental conditions (such as temperature, humidity, light, etc.) meet the storage conditions for different test substances and control samples, and corresponding monitoring records are kept.
7. When test substances and control samples contain volatile, radioactive, or biohazardous materials, there are separate, effectively isolated animal facilities; the management of test substances and control samples, including storage, preparation, disposal, and experimental operations, has corresponding protective facilities and equipment to effectively isolate and protect personnel health.
8. Before conducting research projects involving radioactive and biohazardous materials, the institution must obtain permission from the relevant authorities and have corresponding qualification certification documents.
9. The storage facilities for narcotic drugs, positive control samples (such as teratogenic, carcinogenic, mutagenic compounds), and chemicals that are easy to produce drugs, flammable, explosive, or corrosive, must comply with national regulations.
10. Archive facilities have safety measures against fire, water, moisture, insects, rodents, and theft; computerized archive facilities should also have safety measures against heat, power interruptions, and virus protection; appropriate control and monitoring measures ensure that the environmental conditions of the archive facilities meet the requirements.
11. Facilities and equipment for the disposal or temporary storage of experimental waste.
12. A dual power supply system or backup power source is in place, and the operational status of the backup power source is confirmed regularly.
13. Various facilities have daily hygiene management measures, with regular cleaning and maintenance.
14. An emergency response plan for unexpected events is in place.
15. In case of abnormal facility operation, retain relevant records of abnormal situation handling and reporting; assess the impact on the quality of the research project (if applicable).
（四）Experimental System
Confirm that the institution has an experimental system that matches the applied research and is managed appropriately, ensuring the smooth conduct of experiments and the reliability of experimental data. Key inspection points in this section include but are not limited to:
1. The institution formulates and implements ethical review regulations, retaining review records.
2. The source of purchased experimental animals is clear and compliant, with detailed reception records and retention of relevant certification documents for the quality of experimental animals. Reception records include information such as species, source, arrival date, quantity, and health status of the experimental animals.
3. Experimental animals newly entering the facility have undergone effective isolation and quarantine (or adaptive observation), confirming that their health status meets the requirements of the research project.
4. Sick animals are promptly isolated and treated, and relevant records are retained.
5. Experimental animals have appropriate individual identification, and animal housing cages and rooms have corresponding labels to avoid confusion.
6. The use of experimental animals is recorded, allowing traceability of the reception, use, and disposal of experimental animals, with matching quantities.
7. Animal facilities and animal husbandry supplies (such as cages, racks, water bottles, and other containers) are regularly cleaned and disinfected, using appropriate bedding. The shelf life of sterilized items is verified.
8. Cleaning agents, disinfectants, and insecticides used in animal husbandry rooms have usage records, including name, concentration, usage method, and time of use.
9. Feed, bedding, and drinking water for animals are regularly tested and evaluated, with relevant testing reports and records retained. Sampling for testing is reasonable. The validity period of opened feed and sterilized drinking water is verified.
10. Other experimental systems, apart from experimental animals, have clear sources and detailed reception records. Reception records include information such as name, source, quantity (volume), quality attributes, and reception date; suitability assessments are conducted before use, and relevant records are retained. In case of quality issues, relevant handling and re-evaluation records are retained.
（五）Instruments, Equipment, and Experimental Materials
Confirm that the institution has instruments and equipment that match the applied research and are reliable in performance. Key inspection points in this section include but are not limited to:
1. Equipped with instruments and equipment necessary for the research, with performance meeting usage purposes; equipment is clean and in good condition; an inventory of instruments and equipment is established.
2. The placement of instruments and equipment is reasonable and has status labels.
3. Key instruments and equipment are confirmed or validated to ensure performance meets requirements and is in applicable condition.
4. Detailed records exist for the use, maintenance, testing, calibration, confirmation, or validation of instruments and equipment; usage records reflect the purpose of use (indicating research project name or code information), usage date (recording time of use if necessary), user, instrument and equipment name and/or number; in case of instrument and equipment anomalies, retain relevant records of handling and reporting; assess the impact on the quality of the research project (if applicable).
5. Instruments and equipment used for weighing and preparing test substances and control samples have cleaning measures to prevent cross-contamination, and relevant records are retained.
6. Containers for reagents and solutions are labeled, indicating product name, concentration, storage conditions, preparation date, preparer, and validity period; storage conditions meet requirements.
7. Decomposed or expired reagents and solutions are not used in the research; extensions of the validity period for reagents and solutions have reasonable assessments or analyses, and relevant records are retained.
（六）Test Substances and Control Samples
Confirm that the management and use of test substances and control samples by the institution are appropriate. Key inspection points in this section include but are not limited to:
1. A dedicated person is responsible for the management of test substances and control samples.
2. The management of the reception, storage, distribution, use, sampling, return, or disposal of test substances and control samples complies with SOP requirements and retains complete records.
3. Each batch of test substances and control samples has detailed records of batch numbers, stability, content or concentration, purity, and other physicochemical properties.
4. Containers storing test substances and control samples are labeled appropriately, indicating product name, abbreviation, code or Chemical Abstracts Service (CAS) number, batch number, concentration or content, expiration date, and storage conditions; storage conditions meet requirements; measures are in place to prevent contamination, deterioration, or damage during storage and distribution.
5. Samples of test substances and control samples should meet requirements and be archived.
(VII) SOP
Confirm that the organization has SOPs that are appropriate for the operation of the organization's quality management system and the implementation of research projects. This section's inspection points include but are not limited to:
1. SOPs that are appropriate for the operation of the organization's quality management system and the implementation of research projects, with clear, complete, and operable content; the scope of the SOPs meets requirements.
2. Complete records related to the formulation, revision, review, approval, effectiveness, training, distribution, retrieval, destruction, and archiving of SOPs.
3. SOP revisions are reviewed by QA personnel and take effect after FM approval.
4. SOPs are updated in a timely manner according to current relevant laws, regulations, and technical guidance principles, as well as the organization's operational management and research implementation status, ensuring that SOPs reflect actual operations.
5. Each area is equipped with easily accessible SOPs, all of which are the approved current versions.
(VIII) Implementation of Research Work
By randomly checking research projects, confirm that the entire process of experimental design, organization, implementation, execution, recording, reporting, and archiving meets GLP requirements. This section's inspection points include but are not limited to:
1. Appointment of SD
1.1 The qualifications of the SD meet requirements.
1.2 Before the experiment begins, FM appoints the SD, and there is an SD appointment letter; changes to the SD are made according to prescribed procedures and recorded.
2. Experimental Plan
2.1 The research project has a name or code, and this name or code is used consistently in relevant documents and records.
2.2 The content of the experimental plan should meet requirements. If it involves peer review or multi-site research, the relevant content in the experimental plan or changes to the experimental plan should meet requirements.
2.3 Approval from the animal ethics committee is obtained before implementing the experimental plan.
2.4 The experimental plan and changes to the experimental plan are reviewed by QA personnel.
2.5 The experimental plan and changes to the experimental plan are signed and approved by the SD, with the approval date signed.
2.6 For commissioned research projects, the experimental plan and changes to the plan are recognized by the commissioning party.
2.7 Research personnel and QA personnel obtain copies of the experimental plan and changes to the experimental plan in a timely manner and familiarize themselves with the content of the experimental plan, personnel responsibilities, and work requirements.
2.8 Changes to the experimental plan include the content of the changes, reasons, and dates, and are saved together with the original experimental plan; when research is canceled or terminated, changes to the experimental plan should explain the reasons for cancellation or termination and the method of termination.
3. Implementation of Research
3.1 Staff participating in the research project possess the corresponding qualifications, experience, and capabilities, and strictly implement the experimental plan and related SOP requirements.
3.2 Facilities and Equipment
The necessary experimental facilities and equipment (including computerized systems) for the research project are available; instruments and equipment have been appropriately tested, calibrated, confirmed, or validated, and their performance meets the research project requirements, with relevant records retained. During the implementation of the research project, if there are abnormal operations of facilities or equipment, relevant records of handling and reporting the abnormal situation should be retained, and the impact on the quality of the research project should be assessed.
3.3 Test Substances and Control Samples
3.3.1 Records of the receipt, storage, sampling, distribution, use, and return or disposal of test substances and control samples are complete and quantities match.
3.3.2 The process of preparing mixtures of test substances and control samples with solvents is documented in detail. The storage conditions of the prepared formulations meet requirements, and access records are complete. The stability of the prepared formulations meets requirements, with regular determinations of the concentration and uniformity of test substances and control samples retained.
3.3.3 If the analysis of test substances is conducted by the commissioning party, relevant proof materials for the analysis of test substances should be retained.
3.4 Research Activities
3.4.1 Each research project has a unique name or code, through which test substances, samples, specimens, experimental results, etc., can be traced.
3.4.2 Research activities are conducted according to the experimental plan and related SOPs. For example, in animal experiments, relevant research activities are strictly executed according to the experimental plan and SOP requirements, such as: receiving, isolating, and quarantining (or adapting) animals; numbering, feeding, and grouping animals; treating sick animals; using feed, bedding, and drinking water; preparing and analyzing test substances and control samples; administering substances to animals; observing animals; disposing of discarded animals; collecting and analyzing specimens and original data; re-measuring data; conducting dissections and pathological examinations, etc.
3.4.3 Research records should be timely, accurate, clear, and not easily erased, indicating the date of recording (and time if necessary) and signed by the recorder; data modifications should keep the original record clear and legible, indicating the reason and date for the modification, and signed by the modifier.
3.4.4 Data entered manually into computerized systems should be confirmed.
3.5 For deviations from SOPs and experimental plans that occur, relevant personnel should promptly record and report in writing to the SD (PI); the SD (PI) assesses the impact of the deviation on the reliability of research data and takes corrective and preventive measures if necessary. In multi-site research, the PI promptly feeds back the above situation to the SD.
3.6 Basic information of peer-reviewed pathologists, selected specimens, the process of pathological peer review (such as: slide review records, diagnostic discrepancy reports, and related discussion records, etc.), and peer review statements are documented in detail and traceable.
3.7 Records of sources, quality attributes, preservation, applicability assessment, and use of experimental systems other than laboratory animals are complete.
3.8 When animals show abnormal reactions that require treatment, report to SD in a timely manner and take measures. If medication is needed, it must be approved by SD and the reasons for treatment, examination conditions, medication prescriptions, treatment dates, and results must be recorded in detail.
3.9 For multi-site studies, the research work at each site should comply with GLP requirements.
4. Summary Report
4.1 The content of the summary report should meet the requirements; if it involves peer review, the relevant content of the summary report should meet the requirements; if the research project is canceled or terminated, a brief trial report should be provided.
4.2 The summary report must be signed and approved by SD, with the approval date signed; in multi-site studies, reports from each site must be signed by the PI with the date. The GLP compliance statement must be signed by SD and provide a detailed description of the adherence to GLP during the research process.
4.3 QA personnel review the summary report and sign the QA statement; the inspection plan, inspection records, and inspection report by QA personnel should reflect the situation consistent with the QA statement.
4.4 The summary report includes all deviations from SOP and the study protocol, as well as SD's assessment of the deviations.
4.5 The summary report includes information on the feed, bedding, and drinking water used for the experimental animals.
4.6 The summary report includes the environmental monitoring conditions of the animal facilities during the study period.
4.7 Revisions or supplements to the summary report require approval from SD and review by QA personnel.
4.8 The summary report accurately reflects the original data; the information on test substances and controls, experimental systems, and related indicators, as well as data statistics and result analysis, should be consistent with the original records.
5. Research materials (study protocols, original records and data, specimens, related test reports, samples of test substances and controls, summary reports, and other documents related to the research, electronic materials, etc.) should be archived in a timely manner, and the archived materials should be complete.
(9) Document Archives
Confirm that the institution has effectively managed research and non-research archives. This part of the inspection includes but is not limited to:
1. There is a designated person responsible for archive management.
2. Archiving of research and non-research materials and the frequency of archiving meet the requirements.
3. An archive ledger is established, and archived materials are stored in a classified manner for easy retrieval and search.
4. There are corresponding control measures and records for access to the archive room; personnel must obtain authorization to enter, and there are relevant records for borrowing archives.
5. Electronic data and backup data are complete, readable, easily retrievable, and protected from damage.
(10) Computerized Systems
Confirm that the computerized systems used by the institution for data collection, transmission, storage, processing, archiving, etc. (hereinafter referred to as computerized systems) are managed in accordance with GLP requirements, and the electronic data generated is true, accurate, and complete. This part of the inspection includes but is not limited to:
1. The computerized system is installed appropriately, with necessary virus protection, prevention of unauthorized access, and uninterruptible power supply security measures for hardware, software, servers, and network environments.
2. The computerized system has been validated, and the validation content meets usage requirements; regular reviews are conducted to ensure continued compliance with performance standards; corresponding validation plans, records, reports, and review records are retained.
3. The use and management of the computerized system have different permission allocations, and user permissions match their responsibilities. System user logins are unique and traceable, and corresponding operations can be traced back to individuals.
4. The audit trail function of the computerized system remains enabled, recording relevant information about system operations, including at least: operator, operation time, operation process, operation reason; data generation, modification, deletion, reprocessing, renaming, transfer; changes or modifications to the settings, configurations, parameters, and timestamps of the computerized system. Systems without audit trail functions have corresponding measures to ensure that system activities and data are traceable.
5. Detailed records are kept regarding the handling of failures in the computerized system.
6. Changes to the computerized system (such as hardware replacement, software updates, or system upgrades) have undergone system assessments, and relevant assessment records or reports are retained; if the assessment results require validation, corresponding validation plans, records, and reports are retained.
7. Emergency measures for the computerized system in case of emergencies (such as equipping with uninterruptible power supplies, recording data on paper forms during computer failures or power outages, etc.) are in place.
8. Various system documents, important data, and installation software files (such as foundational system software, database software, application software, etc.) necessary for system recovery are established, and corresponding recovery processes are formulated to ensure that the computerized system can resume operation in the event of catastrophic incidents.
9. When the system is decommissioned, hardware, software, and electronic data should be properly handled, and measures should be taken to ensure that the original system data can be fully accessed and traced within the specified retention period.
10. Electronic data generated by the computerized system is backed up regularly, and the backup and recovery procedures are validated; the sustainability of backup files and media is confirmed regularly, and there are corresponding records for data backup and recovery.
11. Electronic records or data generated by the computerized system are true, accurate, and complete; the processes of data generation, modification, deletion, reprocessing, renaming, and transfer are traceable; the time of the computerized system is true, accurate, and consistent with standard time.
12. Electronic records or data should be signed (using electronic signatures or handwritten signatures after printing); electronic signatures can be traced back to the signer, and signatures cannot be changed or deleted and are only used by the signature owner.
13. The transfer of electronic data is validated to ensure the integrity and consistency of data before and after the transfer.
14. When electronic records coexist with paper records, the form of the original records should be clearly defined.
15. Electronic records or data can be retrieved and accessed at any time during the retention period, with measures in place to prevent unauthorized changes or deletions.
4. Determination Principles
(1) Problem Discovery Levels
Problems discovered are classified into serious defects, major defects, and general defects, with decreasing severity.
1. Serious Defects
Serious defects refer to issues that significantly deviate from GLP requirements, pose major risks, and affect the operation of the institution's quality management system or the reliability of experimental data.
2. Major Defects
Major defects refer to significant deviations from GLP requirements that pose substantial risks and may affect the operation of the institution's quality management system or the reliability of experimental data. Multiple major defects indicate that the institution's quality management system has failed to operate effectively and can be considered serious defects.
3. General Defects
General defects refer to issues that deviate from GLP requirements but have not yet reached the level of serious defects or major defects. Multiple general defects indicate that the institution's quality management system is not operating properly and can be considered major defects.
(2) Principles for Determining Inspection Results
The inspection team classifies the issues found during the on-site inspection and, in conjunction with the principles for determining inspection results, preliminarily assesses whether the institution's quality management system operation and research project implementation comply with GLP requirements. Based on the inspection team's preliminary findings and the institution's submitted rectification report or rectification plan, the verification center conducts a comprehensive evaluation of the institution's GLP implementation. The comprehensive evaluation results are divided into 'complies with GLP requirements' and 'does not comply with GLP requirements.'
1. The following situations may be determined as 'complies with GLP requirements':
1.1 No defects found.
1.2 There are general defects or major defects, but the rectification situation or rectification plan proves that the institution can take effective measures to correct the defects.
2. The following situations may be determined as 'does not comply with GLP requirements':
2.1 Concealing relevant information or providing false materials to apply for GLP certification.
2.2 Refusing or not cooperating with the on-site inspection, resulting in the inability to continue the on-site inspection.
2.3 There are serious defects or multiple major defects considered serious, indicating that the institution's quality management system has failed to operate effectively.
2.4 The rectification report or rectification plan cannot prove that the institution has taken effective measures to correct the defects.
2.5 The rectification report or rectification plan was not submitted within the specified time after the on-site inspection.
2.6 Other non-compliance situations as stipulated by laws and regulations.