21 CFR Part 58 - Good Laboratory Practice (GLP)

If a sponsor terminates or suspends a testing facility from further participation in a nonclinical laboratory study that is part of any application for a research or marketing permit submitted to any Center of the Food and Drug Administration, the sponsor shall notify that Center in writing within 15 working days, stating the reason for the action. Termination by a sponsor is independent of, and neither in lieu of nor a precondition to, proceedings or actions authorised by subpart K.

• Written notification to the relevant FDA Center, dated within 15 working days of the suspension or termination
• Record of the reason for suspending or terminating the facility
• Sponsor procedure covering when a testing facility is suspended or terminated and who must be notified

• Termination recorded internally but never notified to FDA
• Notification sent outside the 15 working day window
• No stated reason for the action in the notification

Establishes the purpose and criteria for disqualifying noncompliant testing facilities.

• Disqualification proceedings file with notice of opportunity for hearing
• Corrective action plan addressing grounds for disqualification
• QA report identifying material non-compliance with Part 58
• Reinstatement petition with supporting evidence package
• Records of post-disqualification audits and verification testing

• QA unit lacks independence from study conduct
• Inadequate SOP coverage or out-of-date SOPs in use
• Training records incomplete for study personnel
• Equipment qualification gaps or expired calibrations

A facility may be disqualified upon FDA finding of repeated failures to comply with GLP requirements.

• Disqualification proceedings file with notice of opportunity for hearing
• Corrective action plan addressing grounds for disqualification
• QA report identifying material non-compliance with Part 58
• Reinstatement petition with supporting evidence package
• Records of post-disqualification audits and verification testing

• QA unit lacks independence from study conduct
• Inadequate SOP coverage or out-of-date SOPs in use
• Training records incomplete for study personnel
• Equipment qualification gaps or expired calibrations

FDA Commissioner issues final order after hearing, precluding facility from conducting future studies.

• Disqualification proceedings file with notice of opportunity for hearing
• Corrective action plan addressing grounds for disqualification
• QA report identifying material non-compliance with Part 58
• Reinstatement petition with supporting evidence package
• Records of post-disqualification audits and verification testing

• QA unit lacks independence from study conduct
• Inadequate SOP coverage or out-of-date SOPs in use
• Training records incomplete for study personnel
• Equipment qualification gaps or expired calibrations

Disqualified facilities may be reinstated upon demonstrating compliance with GLP requirements.

• Disqualification proceedings file with notice of opportunity for hearing
• Corrective action plan addressing grounds for disqualification
• QA report identifying material non-compliance with Part 58
• Reinstatement petition with supporting evidence package
• Records of post-disqualification audits and verification testing

• QA unit lacks independence from study conduct
• Inadequate SOP coverage or out-of-date SOPs in use
• Training records incomplete for study personnel
• Equipment qualification gaps or expired calibrations

Equipment used in generation, measurement, or assessment of data and equipment for facility environmental control must be appropriately designed, of adequate capacity, and suitably located.

• IQ/OQ/PQ records
• Equipment inventory
• URS documents

• Qualification not lifecycle managed
• Equipment used outside operating range
• URS missing for legacy equipment

Equipment must be adequately inspected, cleaned, and maintained. Equipment used for data generation must be tested, calibrated, and standardized according to written SOPs.

• Calibration SOPs
• Calibration records
• PM schedules
• Out-of-tolerance investigations

• Out-of-tolerance impact assessment missing
• PM not scheduled
• Calibration standards not traceable to NIST

A testing facility must have SOPs in writing setting forth nonclinical study methods that management is satisfied are adequate to ensure quality and integrity of data generated.

• SOP index
• SOP review cycle records
• Historical SOP file
• Effective date logs

• SOPs not periodically reviewed
• Historical versions not retained
• No SOP for SOPs

All reagents and solutions in the laboratory areas must be labeled to indicate identity, titer or concentration, storage requirements, and expiration date. Deteriorated solutions must not be used.

• Reagent preparation logs
• Label templates
• Expiry tracking system

• Expired reagents in use
• Preparation traceability missing
• No second-person verification

SOPs must exist for housing, feeding, handling, and care of animals. Newly received animals must be isolated and evaluated to ensure health status. Diseased animals must be isolated.

• Animal husbandry SOPs
• Health observation records
• Veterinary care logs

• Health observations not consistently recorded
• Veterinary intervention records sparse
• Isolation procedures unclear

The testing facility must be of suitable size and construction to facilitate proper conduct of nonclinical studies with separation of activities to prevent disruption that would interfere with studies.

• Facility drawings
• Room use schedules
• Segregation SOPs

• Cross-contamination risk between studies
• No documented room scheduling
• Lab and animal areas insufficiently separated

Sufficient animal care facilities must exist for housing, isolation, quarantine of newly received animals, and routine or specialized housing including means to separate species or test systems.

• Animal facility plans
• Quarantine SOPs
• Health records
• IACUC approvals

• No documented quarantine period
• Health monitoring incomplete
• Cross-species housing risks

Facilities for animal receipt and storage must have adequate quarantine and isolation areas.

• Facility floor plans showing separation of species and study phases
• Animal care SOPs and IACUC approvals
• Environmental monitoring logs (temperature, humidity, airflow)
• Cage wash and sanitation records

• QA unit lacks independence from study conduct
• Inadequate SOP coverage or out-of-date SOPs in use
• Training records incomplete for study personnel
• Equipment qualification gaps or expired calibrations

Separate laboratory space must be provided as needed for performance of routine and specialized procedures required by nonclinical laboratory studies.

• Lab area drawings
• Equipment placement records
• Specialized procedure SOPs

• Inadequate workspace separation
• Specialized areas shared without scheduling
• Cross-contamination controls weak

Laboratories must be separated to prevent cross-contamination and provide suitable conditions for operations.

• Facility floor plans showing separation of species and study phases
• Animal care SOPs and IACUC approvals
• Environmental monitoring logs (temperature, humidity, airflow)
• Cage wash and sanitation records

• QA unit lacks independence from study conduct
• Inadequate SOP coverage or out-of-date SOPs in use
• Training records incomplete for study personnel
• Equipment qualification gaps or expired calibrations

Space must be provided for archives, limited access to authorized personnel only, for orderly storage and expedient retrieval of specimens and data.

• Archive index
• Access logs
• Archivist designation
• Environmental control records

• Archive access not restricted
• No designated archivist
• Environmental conditions not monitored

Defines the scope of GLP regulations for nonclinical laboratory studies supporting FDA applications.

• Master schedule sheet listing all in-scope nonclinical studies
• Study protocol files referencing 21 CFR Part 58 applicability
• GLP applicability determination memoranda from QA unit
• Standard Operating Procedure on GLP scope and definitions

• QA unit lacks independence from study conduct
• Inadequate SOP coverage or out-of-date SOPs in use
• Training records incomplete for study personnel
• Equipment qualification gaps or expired calibrations

Establishes that GLP requirements apply to studies performed under grants and contracts.

• Master schedule sheet listing all in-scope nonclinical studies
• Study protocol files referencing 21 CFR Part 58 applicability
• GLP applicability determination memoranda from QA unit
• Standard Operating Procedure on GLP scope and definitions

• QA unit lacks independence from study conduct
• Inadequate SOP coverage or out-of-date SOPs in use
• Training records incomplete for study personnel
• Equipment qualification gaps or expired calibrations

Authorizes FDA to inspect testing facilities to verify GLP compliance at reasonable times.

• FDA Form 483 history and Establishment Inspection Reports
• Inspection readiness checklist and mock inspection records
• QA inspection program schedule and findings log
• Management response letters to inspection observations

• QA unit lacks independence from study conduct
• Inadequate SOP coverage or out-of-date SOPs in use
• Training records incomplete for study personnel
• Equipment qualification gaps or expired calibrations

Provides definitions of key terms used throughout the regulation including study director, sponsor, and test article.

• Master schedule sheet listing all in-scope nonclinical studies
• Study protocol files referencing 21 CFR Part 58 applicability
• GLP applicability determination memoranda from QA unit
• Standard Operating Procedure on GLP scope and definitions

• QA unit lacks independence from study conduct
• Inadequate SOP coverage or out-of-date SOPs in use
• Training records incomplete for study personnel
• Equipment qualification gaps or expired calibrations

Personnel engaged in nonclinical laboratory studies must have appropriate education, training, and experience. Current summaries of training, experience, and job descriptions must be maintained.

• CVs
• Training records
• Job descriptions
• Training matrix
• Qualification statements

• Training not study-specific
• CVs not current
• Refresher training missing

Testing facility management must designate a Study Director, ensure a Quality Assurance Unit exists, ensure test and control articles are characterized, and that deviations are documented.

• Org chart
• Management review records
• QAU charter
• Study Director appointment letters

• Management review not periodic
• QAU not independent
• Study Director appointments not documented

For each nonclinical study, a scientist with appropriate education, training, and experience must be identified as the Study Director with overall responsibility for technical conduct, interpretation, analysis, and reporting.

• Study Director CV
• Designation memos
• Study protocols
• Final reports signed by SD

• SD not designated in writing
• SD lacks bench involvement
• Multiple uncoordinated SDs

A QAU must be entirely separate from study personnel. The QAU maintains a master schedule, audits each study at intervals, and reports findings in writing to management and the Study Director.

• QAU SOPs
• Master schedule
• Audit reports
• Audit checklists
• Statement of compliance

• QAU not independent of operations
• Master schedule incomplete
• No phase inspections

A final report must be prepared for each study with prescribed content including name and address of facility, dates, objectives, methods, deviations, statistical methods, results, and Study Director signature.

• Final reports
• QA statements
• Statistical analysis plans
• Amendment to final reports

• Deviations not addressed in report
• QA statement missing dates
• Statistical methods not preplanned

All raw data, documentation, protocols, final reports, and specimens generated as a result of a nonclinical laboratory study must be retained in archives for orderly storage and expedient retrieval.

• Archive index
• Indexing system
• Specimen storage logs
• Retrieval request logs

• Index incomplete
• Specimens not retrievable in reasonable time
• Electronic archives unverified for readability

Documentation records, raw data, and specimens must be retained for periods specified including five years following marketing application approval or two years following submission date.

• Retention schedules
• Disposition records
• Sponsor transfer letters

• Retention clock not tracked per study
• Sponsor transfer without acknowledgment
• Early destruction risk

Identity, strength, purity, and composition or other characteristics to define test and control articles must be determined for each batch and documented. Stability must be determined before initiation or concomitantly.

• CoAs
• Characterization reports
• Stability data
• Reserve samples

• Stability determined post-hoc with no justification
• Reserve samples not retained
• Identity not confirmed each batch

Procedures must exist for proper storage, distribution, identification, and documentation of receipt of test and control articles. Records of distribution must be maintained.

• Receipt logs
• Distribution records
• Storage condition logs
• Reconciliation records

• Reconciliation discrepancies unresolved
• Storage temperature gaps
• Chain of custody breaks

For each test or control article that is mixed with a carrier, tests by appropriate analytical methods must be conducted to determine uniformity, concentration, and stability of mixtures.

• Mixture analysis reports
• Method validation for mixtures
• Stability of mixtures data

• Homogeneity not tested at top/middle/bottom
• Stability of mixture not established
• Concentration drift unverified

Each study must have an approved written protocol that clearly indicates objectives and all methods for conduct. The protocol must contain specified elements and be signed by the Study Director.

• Approved protocols
• Protocol amendments
• Protocol deviation logs

• Amendments unsigned
• Deviations not classified by impact
• Required elements missing

The study must be conducted in accordance with the protocol. All data must be recorded directly, promptly, and legibly in ink. Each data entry must be dated and signed or initialed.

• Raw data records
• Corrections audit trail
• Electronic data audit trails

• Corrections without reason and date
• Pencil entries
• Electronic system audit trails not reviewed